Drug delivery device with intravesical tolerability

ABSTRACT

Intravesical devices are provided that are wholly deployable within the bladder of a patient in need of treatment and are well tolerated by the patient. The device may include an elastic body having a retention shape having (i) dimensions that provide intravesical mobility and that prevent voiding of the medical device through the urethra, and (ii) dimensions, buoyancy, or both, that exclude the medical device from entering the orifices of the ureters. The elastic body may exert a maximum acting force less than 1N when compressed to a shape with a maximum dimension in any dimension of 3 cm. The device may include a drug for controlled release within the bladder, for treatment of the bladder or a regional tissue. Methods of treatment are also provided that include selecting a patient in need of treatment in the bladder where tolerability of the treatment is a primary concern.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/224,256, filed Mar. 25, 2014, which is a continuation of U.S.application Ser. No. 12/972,364, filed Dec. 17, 2010, which claimspriority to U.S. Provisional Application No. 61/287,649, filed Dec. 17,2009, and U.S. Provisional Application No. 61/325,713, filed Apr. 19,2010, each of which is incorporated by reference herein in its entirety.

BACKGROUND

This disclosure is generally in the field of implantable medical devicesand methods, more particularly in the field of drug delivery devicesdeployable within the bladder.

Systemic methods of drug delivery may produce undesirable side effectsand may result in the distribution and metabolization of the drug byphysiological processes, ultimately reducing the quantity of drug toreach the desired site. A variety of devices and methods have beendeveloped to deliver drug in a more targeted manner, e.g., locally orregionally, which may address many of the problems associated withsystemic drug delivery. Local delivery of drug to some tissue sites,however, has room for improvement, particularly with respect to extendeddrug delivery with minimally invasive devices and method and withminimum patient discomfort.

Interstitial cystitis (IC), painful bladder syndrome (PBS), and chronicprostatitis/chronic pelvic pain syndrome (CP/CPPS) are chronic painfuldisorders that are often treated by delivering a lidocaine solution tothe bladder via instillation. To achieve sustained relief, repeatedinstillations may be required, such as three times per week for twoweeks. The frequency of such instillations may be undesirable, as eachinstillation entails the inconvenience, discomfort, and risk ofinfection associated with urinary catheterization. Similarly,intermittent catheterization may be used to deliver drugs to the bladderthat ease symptoms of neurogenic bladder. However, catheterizationcarries the drawbacks described above, among others. Thus, treatmentscould benefit from an intravesical drug delivery device that isimplanted in the bladder.

Other therapies also could benefit from improved intravesical drugdelivery devices, particularly where local delivery of a drug to thebladder is preferred or necessary—such as when the side effectsassociated with systemic delivery of the drug are intolerable and/orwhen bioavailability from oral administration is too low.

Situs Corporation developed an intravesical drug delivery system (UROSinfuser device) for the delivery of pharmaceutical solutions of drugs,such as oxybutynin (for the treatment of overactive bladder) andmitomycin C (for the treatment of bladder cancer). The UROS infuserdevice and methods of implanting the device are disclosed in U.S. Pat.Nos. 6,171,298, 6,183,461, and 6,139,535. One problem with such devicesis that the device is relatively large because a relatively large volumedevice is required to contain both a sufficient amount of the drugsolution and the inlet/outlet valve mechanism.

Previous attempts at bladder drug delivery devices show thattolerability of the device in the bladder is a patient concern and atechnical hurdle. For certain conditions or diseases, such as where thedisease or condition is potentially fatal if left untreated (e.g.,cancer), tolerability may be a secondary consideration. However, forother indications, tolerability may be a primary consideration.Unfortunately, known bladder devices, due perhaps to their large size orother mechanical characteristics, have not been well tolerated bypatients and would be unsuitable in indications where tolerability is aprimary concern, particularly where the treatment process wouldadvisably require deployment and drug release over an extended period.

A need therefore exists for an intravesical drug delivery device that issufficiently small to avoid unnecessary discomfort and pain during andfollowing deployment of the device into patients, that can reduce thenumber of surgical or interventional procedures required forimplantation and delivery of drug over the treatment period—e.g., thatprovides controlled delivery over an extended period, and that can carryan effective amount of drug for the extended period in a sufficientlysmall payload volume. In bladder applications, the device desirablyshould be retained in the bladder and not excreted before the drugpayload can be at least substantially released, even when the drug needsto be delivered over a period of several days or weeks. In general,better devices are needed for controlled delivery of drug to thebladder. Desirably, the implantable device should be easy to deliverinto (and if necessary, remove from) the bladder with reduced pain ordiscomfort to the patient.

SUMMARY

Improved intravesical devices and methods of treatment are provided. Inone aspect, a medical device is provided that is wholly deployablewithin the bladder of a patient, such as a human, in need of treatmentand is well tolerated by the patient. In one embodiment, the deviceincludes an elastic body having a retention shape having (i) dimensionsthat provide intravesical mobility and that prevent voiding of themedical device through the urethra, and (ii) dimensions, buoyancy, orboth, that exclude the medical device from entering the orifices of theureters. The elastic body may exert a maximum acting force less than 1 Nwhen compressed to a shape with a maximum dimension in any dimension of3 cm, or 1.5 cm. The device in the retention shape and uncompressed mayhave a maximum dimension in any direction that is less than 10 cm, suchas less than 5 cm. The device in a dry state may have a density of about1.5 g/mL or less, such as about 0.5 g/mL to about 1.3 g/mL. In oneembodiment, the elastic body houses or otherwise includes a drug forcontrolled release within the bladder. In a preferred embodiment, thedrug is part of a formulation that is in the form of a plurality ofcompressed tablets housed in the elastic body.

In one aspect, a drug delivery device is provided which is whollydeployable within the bladder of a human patient and well tolerated bythe patient. The device includes an elastic body housing a solid drugformulation, wherein the device is deformable between a deployment shapefor passage of the device through the urethra and a retention shape forpreventing voiding of the device through the urethra, the retentionshape having a maximum dimension in any dimension of 5 cm when in anuncompressed state and wherein the device exerts a maximum acting forceless than 1 N when the retention shape is compressed to a shape having amaximum dimension in any dimension of 3 cm. The drug formulation maycomprise lidocaine, another anesthetic, or another drug.

In another aspect, a method of treatment of a human patient is provided,which method includes (i) selecting a patient in need of treatment inthe bladder where tolerability of the treatment is a primary concern;(ii) deploying a drug delivery device into the patient's bladder throughthe patient's urethra; and (iii) releasing a drug into the bladder fromthe deployed drug delivery device over a treatment period. In oneembodiment, the patient cannot feel the deployed device within his orher bladder during at least a majority of the treatment period. Theselected patient may be indicated to be in need of treatment foroveractive bladder; painful bladder syndrome; interstitial cystitis; aninfection of the bladder, prostate, or urethra; neurogenic bladder;prostatitis or urethritis; or perioperative or postoperative painassociated with a urological surgery on the patient.

In another aspect, a method is provided for treating a genitourinarytissue site in a patient. In one embodiment, the method includesdeploying a drug delivery device into the bladder of the patient; andreleasing a drug from the drug delivery device into the bladder in anamount and at a rate to administer a therapeutically effective amount ofthe drug to at least one genitourinary tissue site other than thebladder. For example, the genitourinary tissue sites may be the urethra,ureter, kidneys, penis, testes, prostate, seminal vesicles, ejaculatoryducts, vas deferens, vagina, uterus, ovaries, fallopian tubes, or acombination thereof. The method may include selecting a patient in needof treatment where tolerability of the drug delivery device to bedeployed in the bladder is a primary concern. The drug may includelidocaine or another anesthetic agent. The selected patient may beindicated to be in need of treatment for perioperative or postoperativepain associated with a urological surgery on the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of an embodiment of a drug delivery device.

FIG. 2 is a plan view of the drug delivery device shown in FIG. 1,illustrating the drug delivery device inside a deployment instrument.

FIG. 3 is a cross-sectional view of the drug delivery device shown inFIG. 1, taken along line 3-3 in FIG. 1.

FIG. 4 is an illustration showing the size of an embodiment of a drugdelivery device in comparison to an approximation of the bladder trigoneregion.

FIG. 5 illustrates examples of shapes for a retention frame of a drugdelivery device.

FIG. 6 illustrates examples of configurations for drug delivery deviceshaving at least one drug delivery portion and a retention frame portion.

FIG. 7 illustrates a method of implanting a drug delivery device.

FIG. 8 is a sagittal view of a male patient, illustrating a drugdelivery device exiting a deployment instrument into a bladder of thepatient.

FIG. 9 is a detailed cross-sectional plan view of an embodiment of adrug delivery device.

FIG. 10 is a detailed cross-sectional plan view of another embodiment ofa drug delivery device.

FIG. 11 is a graph compression along the long axis for various devices,meaning compression that tends to change the shape of the device alongits longer axis as a compressive force is applied to the device alongits longer axis.

FIG. 12 is a graph that illustrates compression along the short axis forvarious devices, meaning compression that tends to change the shape ofthe device along its shorter axis as a compressive force is applied tothe device along its shorter axis.

FIG. 13 is a biodistribution graph for a study conducted in vivo inrabbit, illustrating the tissue concentration of lidocaine at varioussampled locations.

DETAILED DESCRIPTION

Implantable devices are provided that can be implanted in a lumen orbody cavity of a patient, such as the bladder or another genitourinarysite, for release of one or more drugs over an extended period. It wasunexpectedly and beneficially discovered that an intravesical devicehaving certain attributes can when wholly deployed within the bladder ofa patient be well tolerated by the patient. In fact surprisingly in someembodiments, the presence of the device in the bladder may beunnoticeable to the patient. The device has a combination ofcharacteristics that facilitate both its functionality and tolerability.These characteristics, as detailed below, include the size and shape ofthe device in combination with its compressibility and in some cases itsthe density, among others, which determine how mobile the device iswithin the bladder and to what degree the device contacts the trigoneregion or bladder wall.

Generally, it is believed that the more mobile the device is, then themore tolerable the device is. In addition, the dimensions are largeenough to prevent voiding of the medical device through the urethra andto prevent the medical device from entering the orifices of the ureters.Another characteristic is the density of the device, which determines,for example, whether the device will float in urine in the bladder,which also impacts how the device feels in the patient's bladder. Stillanother characteristic that is believed to bear on tolerability is thestiffness, or spring constant, of the device when in its deployed shape.The device, in a preferred embodiment, has a size, shape, and/or minimumspring constant sufficient to prevent voiding of the medical device fromthe bladder. For example, it should not be so pliable (i.e., have such alow spring constant) that hydrodynamic forces during urination areeffective to cause the device to bend or reshape into a low-profileconfiguration that would permit the device to pass from the bladderduring urination. In addition, the device should not be so stiff andunpliable that it causes discomfort or pain to the patient when thedevice contacts the bladder wall.

Another aspect of the tolerability discovery is that certain therapiestherefore advantageously become suitable for human patient populationsfor whom tolerability of the device in the bladder is primary concern.

The implantable device is designed for deployment into and retentionwithin a portion of the body, such as the bladder. The device may beflexible so that the device can be deformed for insertion, yet onceimplanted the device may resist excretion in response to the forces ofurination or other forces. In particular embodiments, an implantabledrug delivery device is loaded with one or more drugs in the form of anumber of solid drug units, such as tablets or pellets. Advantageously,the drug loaded device in a preferred embodiment is flexible ordeformable despite being loaded with solid drug, as each drug unit maybe permitted to move with reference to adjacent drug units.

In particular embodiments, the drug delivery device is small, such assmall enough to be inserted through a deployment instrument extendingthrough the urethra into the bladder. Such a device may be loaded withsolid drug tablets that are substantially smaller than conventional drugtablets, and unlike conventional tablets the drug tablets also mayconstitute mostly drug and little or no excipients, so that the drugtablets contain a large amount of drug considering the tablet size. Inparticular embodiments, the drug delivery device may deliver lidocaineor another cocaine analogue locally to the bladder over a relativelyextended period for the treatment of a condition such as IC/PBS,neurogenic bladder, or pain such as post-operative pain.

The device may be implanted non-surgically and may deliver drug longafter the implantation procedure has ended. For example, the device maybe deployed through a deployment instrument, such as a catheter orcystoscope, positioned in a natural lumen of the body, such as theurethra, into a body cavity, such as the bladder.

The drug delivery device may deliver drug locally and/or regionally toone or more genitourinary sites within the body. The device may bewholly implanted in the bladder to deliver drug locally to the bladderand regionally to nearby sites. Thus, drug delivery to one genitourinarysites can be achieved using a drug delivery device implanted in anothergenitourinary site.

When implanted in the bladder, the device overcomes many deficiencies ofconventional treatments, such as delivery via instillation, which mustbe repeated; delivery via conventional devices, which must be re-filledonce implanted; delivery via catheters, which provide a path forbacteria to migrate into the bladder, and systemic delivery, with itsassociated risk of side effects and reduced drug delivery to the targetsite. On the contrary, the present device can be implanted once and canrelease drug over an extended period without surgery or frequentinterventions, reducing the opportunity for infection and side effects,increasing the amount of drug delivered locally or regionally to thebladder, and improving the quality of life of the patient during thetreatment process. Thereafter, the device may be removed. Alternatively,the device may be partially or substantially bioerodible so that aninvasive retrieval procedure can be avoided.

The devices and methods disclosed herein may be adapted for use inhumans, whether male or female, adult or child, or for use in animals,such as for veterinary or livestock applications.

The devices and methods disclosed herein build upon those described inthe following U.S. patent applications, which are incorporated byreference herein: U.S. application Ser. No. 11/463,956, filed Aug. 11,2006; U.S. application Ser. No. 12/333,182, filed Dec. 11, 2008; U.S.application Ser. No. 12/538,580, filed Aug. 10, 2009; U.S. applicationSer. No. 12/825,215, filed Jun. 28, 2010; U.S. application Ser. No.12/825,238, filed Jun. 28, 2010; U.S. application Ser. No. 12/851,494,filed Aug. 5, 2010; U.S. application Ser. No. 12/870,261, filed Aug. 27,2010; PCT US 2010/48266, filed Sep. 9, 2010; U.S. application Ser. No.12/879,638, filed Sep. 10, 2010; U.S. application Ser. No. 12/963,621,filed Dec. 8, 2010; U.S. Provisional Application No. 61/311,103, filedMar. 5, 2010; U.S. Provisional Application No. 61/370,902, filed Aug. 5,2010; U.S. Provisional Application No. 61/371,139, filed Aug. 5, 2010;U.S. Provisional Application No. 61/390,495, filed Oct. 6, 2010; U.S.Provisional Application No. 61/390,549, filed Oct. 6, 2010; and U.S.Provisional Application No. 61/405,379, filed Oct. 21, 2010.

I. The Implantable Drug Delivery Device

An embodiment of a drug delivery device 100 is illustrated in FIG. 1.The device 100 includes a drug reservoir portion 102 and a retentionframe portion 104. In FIG. 1, the device 100 is shown in a relativelyexpanded shape suited for retention in the body, and in FIG. 2 thedevice 100 is shown in a relatively lower-profile shape for deploymentthrough the channel 200 of a deployment instrument, such as a cystoscopeor other catheter. Following deployment into the body, the device 100may assume the relatively expanded shape to retain the drug deliverydevice in the body cavity or lumen.

For the purposes of this disclosure, terms such as “relatively expandedshape”, “relatively higher-profile shape”, or “retention shape”generally denote any shape suited for retaining the device in theintended implantation location, including but not limited to the pretzelshape shown in FIG. 1 that is suited for retaining the device in thebladder. Similarly, terms such as “relatively lower-profile shape” or“deployment shape” generally denote any shape suited for deploying thedrug delivery device into the body, including the linear or elongatedshape shown in FIG. 2 that is suited for deploying the device throughthe working channel of catheter, cystoscope, or other deploymentinstrument positioned in a lumen of the body, such as the urethra. Inembodiments, the drug delivery device may naturally assume therelatively expanded shape and may be deformed, either manually or withthe aid of an external apparatus, into the relatively lower-profileshape for insertion into the body. Once deployed the device mayspontaneously or naturally return to the initial, relatively expandedshape for retention in the body.

In the illustrated embodiment, the drug reservoir and retention frameportions 102, 104 of the drug delivery device 100 are longitudinallyaligned and are coupled to each other along their length, although otherconfigurations are possible. For example, the drug reservoir portion 102may be attached to the retention frame portion 104 at discrete pointsbut otherwise may be separate or spaced apart from the retention frameportion 104.

In particular, the drug delivery device 100 includes an elastic orflexible device body 106 that defines a drug reservoir lumen 108 and aretention frame lumen 110. The drug reservoir lumen 108 is designed tohouse a drug formulation, such as a number of solid drug tablets 112, toform the drug reservoir portion 102. The retention frame lumen 110 isdesigned to house a retention frame 114 to form the retention frameportion 104. The illustrated lumens 108, 110 are discrete from eachother, although other configurations are possible.

As shown in the cross-sectional view of FIG. 3, the device body 106includes a tube or wall 122 that defines the drug reservoir lumen 108and a tube or wall 124 that defines the retention frame lumen 110. Thetubes 122, 124 and lumens 108, 110 can be substantially cylindrical,with the drug reservoir lumen 108 having a relatively larger diameterthan the retention frame lumen 110, although other configurations can beselected based on, for example, the amount of drug to be delivered, thediameter of the retention frame, and deployment considerations such asthe inner diameter of the deployment instrument. The device body 106 maybe formed integrally, such as via molding or extrusion, althoughseparate construction and assembly of the tubes 122, 124 is possible.The wall 124 that defines the retention frame lumen 110 may extend alongthe entire length of the wall 122 that defines the drug reservoir lumen108, so that the retention frame lumen 110 has the same length as thedrug reservoir lumen 108 as shown, although one wall may be shorter thanthe other wall in other embodiments. Further, the two walls 122, 124 areattached along the entire length of the device in the illustratedembodiment, although intermittent attachment can be employed. In oneexample, the wall 122 of the drug reservoir lumen 108 has an innerdiameter of about 1.5 mm and an outer diameter of about 1.9 mm, whilethe wall 124 of the retention frame lumen 110 has an inner diameter ofabout 0.5 mm and an outer diameter of about 0.9 mm. The cross-sectionalarea of the entire body of the device 106 may be about 0.035 cm² orless.

An aperture 118 may be formed through the wall 124 that defines the drugreservoir lumen 108. The aperture 118 may provide a passageway forreleasing drug from the drug reservoir lumen 108 as further describedbelow. However, the aperture 118 may be omitted in some embodiments.

As shown in FIG. 1, the drug reservoir lumen 108 is loaded with a numberof drug units 112 in a serial arrangement. For example, between about 10and about 100 drug units 112 may be loaded, such as between about 30 andabout 70 drug units 112, or more particularly between about 50 and 60drug units 112. However, any number of drug units may be used. The drugreservoir lumen 108 includes an entry 130 and an exit 132, which areshown as relatively circular openings at opposite ends of the drugreservoir lumen 108. The entry 130 provides ingress for the drug units112 to be placed into the drug reservoir lumen 108 during device loadingand assembly, such as by a flow of pressurized gas, in which case theexit 132 provides egress for the flow of pressurized gas to escape fromthe drug reservoir lumen 108. Once the drug units 112 are loaded, atleast two end plugs 120 block the entry 130 and exit 132. The end plugs120 may be cylindrical plugs inserted into the entry 130 and the exit132, each having a slightly larger outer diameter than an inner diameterof the drug reservoir lumen 108 so that the plugs substantially enclosethe entry 130 and exit 132 and are snugly retained in position. In somecases, a number of end plugs 120 can be positioned in the entry 130 orthe exit 132. The end plugs 120 may be silicone plugs. The end plugs 120also may be omitted, in which case the entry 130 and exit 132 may beclosed with a material, such as adhesive, that is placed in the drugreservoir lumen 108 in workable form and cures therein.

In some embodiments, the drug tablets 112 may not fill the entire drugreservoir lumen 108. In such embodiments, a filling material may be usedto fill the remainder of the drug reservoir lumen 108. For example, thedrug tablets 112 may be loaded in a central portion of the drugreservoir lumen 108 and the filling material may be loaded in theremaining end portions of the drug reservoir lumen 108. The fillingmaterial may be inserted into the end portions of the drug reservoirlumen 108 after the lumen is filled with the drug tablets 112. Thefilling material may be a polymeric material. The polymeric material maybe placed in the drug reservoir lumen 108 in workable form and may curetherein. Suitable polymeric materials may cure at room temperature or inresponse to an external stimulus, such as heat. In some cases, thefilling material may enclose the entry 130 and exit 132, in which casethe end plugs 120 may or may not be provided. The filling material alsomay be a number of end plugs 120 inserted into the end portions of thedrug reservoir lumen 108.

Once the drug units 112 are loaded, interstices 116 or breaks may beformed between adjacent drug units 112. The interstices or breaks 116may serve as reliefs that accommodate deformation or movement of thedevice 100, while permitting the individual drug units 112 to retaintheir solid form during storage and deployment. Thus, the drug deliverydevice 100 may be relatively flexible or deformable despite being loadedwith a solid drug, as each drug unit 112 may be permitted to move withreference to adjacent drug units 112. Along the length of the devicedrug reservoir lumen 108, the drug units 112 may have the samecomposition or may vary in composition, and in some cases drug units 112of different compositions may be in distinct reservoirs that aresegregated, either axially or radially, along the length of the drugreservoir lumen 108.

The retention frame lumen 110 is loaded with the retention frame 114,which may be an elastic wire. The retention frame 110 may be configuredto spontaneously return to a retention shape, such as the illustrated“pretzel” shape or another coiled shape. In particular, the retentionframe 114 may retain the device 100 in the body, such as in the bladder.For example, the retention frame 114 may have an elastic limit andmodulus that allows the device 100 to be introduced into the body in arelatively lower-profile shape, permits the device 100 to return therelatively expanded shape once inside the body, and impedes the devicefrom assuming the relatively lower-profile shape within the body inresponse to expected forces, such as the hydrodynamic forces associatedwith contraction of the detrusor muscle and urination. Thus, the device100 may be retained in the body once implanted, limiting or preventaccidental expulsion.

The material used to form the device body 106 may be elastic or flexibleto permit moving the device 100 between deployment and retention shapes.When the device is in the retention shape, the retention frame portion104 may tend to lie inside the drug reservoir portion 102 as shown,although the retention frame portion 104 can be positioned inside,outside, above, or below the drug reservoir portion 102 in other cases.The flexible material also allows the device body 106 to flex outward orcircumferentially expand in response to a flow of pressurized gasthrough the drug reservoir lumen 108 during drug loading, as describedbelow. The material used to form the device body 106 also may be waterpermeable or porous so that solubilizing fluid can enter the drugreservoir portion 102 to solubilize the drug units 112 once the deviceis implanted. For example, silicone or another biocompatible elastomericmaterial may be used.

In one embodiment in which the drug delivery device 100 is designed tobe implanted in the bladder, the drug delivery device 100 is designed tobe inserted into (and optionally retrieved from) the bladder through theurethra cystoscopically. Thus, the device may be sized and shaped to fitthrough a narrow tubular path of a deployment instrument, such as acatheter or cystoscope. Typically, a cystoscope for an adult human hasan outer diameter of about 5 mm and a working channel having an innerdiameter of about 2.4 mm to about 2.6 mm. In embodiments, a cystoscopehaving a working channel with a larger inner diameter, such as an innerdiameter of 4 mm or more. Thus, the device may be relatively small insize. For example, when the device is elastically deformed to therelatively lower profile shape, the device for an adult patient may havea total outer diameter that is less than about 2.6 mm, such as betweenabout 2.0 mm and about 2.4 mm. For pediatric patients, the dimensions ofthe device are anticipated to be smaller, e.g., proportional for examplebased on the anatomical size differences and/or on the drug dosagedifferences between the adult and pediatric patients. In addition topermitting insertion, the relatively small size of the device may alsoreduce patient discomfort and trauma to the bladder.

The overall configuration of the device facilitates ensuring the deviceis tolerable to the patient. It should be noted that the device may betolerable to the patient while still being noticeable. The device isboth tolerable and unnoticeable in preferred embodiments, while in otherembodiments the device is tolerable but noticeable. A noticeable devicemay nonetheless be tolerable to the patient if the device isappropriately configured. For example, the device may be configured toreduce the likelihood of contacting the bladder wall and to reduce thepressure exerted by the device on the bladder wall when contact doesoccur. Bladder wall contact may cause bladder irritation that isuncomfortable for some patients and may be unbearable for sensitivepatients, such as those suffering from IC/PBS. Thus, noticeability andtolerability may vary depending on differences in patient anatomy andperception of pain and discomfort. However, the overall configuration ofthe device may ensure tolerability for most patients.

To facilitate tolerability, the size of the device may be smaller thanthe bladder under most levels of bladder fullness. The size of the humanbladder changes depending on whether the bladder is full or empty. Forexample, a typical bladder may hold about 500 mL when full and about 0to 30 mL when empty, such as about 15 mL. The bladder is roughlyspherical when full and varies in shape when empty or nearly empty,often assuming a roughly ellipsoidal shape when empty. A typical fullbladder may have a diameter of about 10 cm to about 13 cm, while anempty bladder may have dimensions of about 3×4×2 cm, although thedimensions of the empty bladder may vary by as much as about 2 cm in anydirection. For example, an empty bladder may have dimensions of about5×5×1 cm. For the purposes of this disclosure, the diameter of the emptybladder is approximated to be about 3 cm, as the typical empty bladdermay have a dimension of about 3 cm in at least one direction.

The fullness of the bladder also affects the intravesical pressuretherein. The bladder pressure is sensed by nerves in the bladder wall sothat a sense of bladder fullness and a desire to void are appropriatelycreated. Typically, when the bladder contains between about 100 and 200mL of urine, the pressure within the bladder is between about 8 and 15cm H₂O (about 0.79 to 1.47 kPa). At these pressures the first sensationof bladder fullness occurs, while lower pressures are mediated by nervesin the bladder wall so that no sensation of bladder fullness is created.As the bladder becomes full, a definite sensation of bladder fullnessand an urge to urinate may be created. A full bladder may correspond tointravesical pressures of about 40 and 100 cm H₂O (about 3.92 kPa to 9.8kPa).

More particularly, the sensation of an urge to urinate is created withinthe bladder trigone region, which is an area of the bladder definedbetween the bladder neck and the ureteral orifices. The trigone can beapproximated as a triangle having a top vertex that represents thebladder neck and two bottom vertices that represent the ureteralorifices. FIG. 4 shows an example triangle that approximates the trigoneof an adult human male. In a human male, the distance from the bladderneck to one of the ureteral orifices is about 2.75 cm and the distancebetween the two ureteral orifices is about 3.27 cm. Thus, in FIG. 4, thedistance from the top vertex to either of the bottom vertices is about2.8 cm, while the distance between two bottom vertexes is 3.3 cm. Thesize of the trigone region may vary depending on the animal. In an adultfemale, for example, the distance between the two ureteral orifices isabout 2.68 cm and the distance from a neck of the bladder to one of theureteral orifices is about 2.27 cm. Smaller animals may have smallertrigone regions.

In view of these bladder characteristics, the device is configured to betolerable within the bladder. In particular, the device is sized so thatwhen the device is in the retention shape, the device is smaller thanthe bladder under most conditions of bladder fullness. A device that issmaller than the bladder under most conditions of bladder fullness mayhave reduced contact with the bladder wall, reducing irritation of thebladder wall and contact pressure that may be sensed as bladderfullness. However, when the device is in the retention shape, the devicemay have an overall size and shape that is selected so that when thedevice overlays the triangular approximation of the bladder trigoneregion, the device is larger than the triangular approximation. Suchsizing limits the ability of the device to come to rest within thetrigone region, which may be sensitive. Such sizing also limits thelikelihood of a portion of the device entering or becoming trappedwithin the bladder neck and the ureteral orifices.

In some embodiments, the device in a retention shape may have dimensionsin all directions that are less than 3 cm, so that when the bladder isempty, the device does not necessarily have to contact the bladder wallto fit within the bladder. In other embodiments, the device in theretention shape may have at least one dimension that is larger than 3cm, so that a larger drug payload can be delivered. In such embodiments,the bladder wall may exert a pressure on the device that compresses thedevice in at least one direction so that it fits within the emptybladder, and the compressed device may exert a return pressure on thebladder wall. The return pressure may not exceed those pressuresassociated with a sensation of urgency of urination or bladder fullness,so that the device remains tolerable. Thus, the size and shape of thedevice may be selected so that when the device is compressed, the deviceexerts a pressure on the bladder wall that is less than about 9.8 kPa.In some embodiments, the size and shape of the device may be selected sothat when the device is compressed, the device exerts a pressure on thebladder wall that is less than about 3.92 kPa. In particularembodiments, the size and shape of the device may be selected so thatwhen the device is compressed, the device exerts a pressure on thebladder wall that is less than about 1.47 kPa and may be less than 0.79kPa. These pressures can be achieved by varying the overall size of thedevice and the extent of its surface area. For example, the surface areaof the device may be increased to decrease the pressure exerted againstthe bladder wall upon contact, although the overall cross-sectional areaof the device may not be increased above a size that is deployablethrough the urethra.

It is possible to approximate the compression forces that the bladdermay impose upon the device without the device in turn exposing thebladder to a pressure that exceeds the outer limit of 9.8 kPA, and moreparticularly 1.47 kPa. For example, a spherical device positioned in aspherical bladder is in contact with the bladder wall about its equator.Such a device can be approximated as exerting a pressure on the bladderwall of about 9.8 kPa when the bladder compresses the device with atotal compressive force of about 7 N. Similarly, such a device can beapproximated as exerting a pressure on the bladder wall of about 1.47kPa when the bladder compresses the device with a total compressiveforce of about 1 N. Of course, devices with other, smaller surface areascan exert comparable pressures on the bladder while absorbing smallercompressive loads.

Thus, within the three-dimensional space occupied by the device in theretention shape, the maximum dimension of the device in any direction isless than 10 cm, the approximate diameter of the bladder when filled. Insome embodiments, the maximum dimension of the device in any directionmay be less than about 9 cm, such as about 8 cm, 7 cm, 6 cm, 5 cm, 4.5cm, 4 cm, 3.5 cm, 3 cm, 2.5 or smaller. In particular embodiments, themaximum dimension of the device in any direction is less than about 7cm, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm orsmaller. In preferred embodiments, the maximum dimension of the devicein any direction is less than about 6 cm, such as about 5 cm, 4.5 cm, 4cm, 3.5 cm, 3 cm, 2.5 cm or smaller.

More particularly, the three-dimension space occupied by the device isdefined by three perpendicular directions. Along one of these directionsthe device has its maximum dimension, and along the two other directionsthe device may have smaller dimensions. For example, the smallerdimensions in the two other directions may be less than about 4 cm, suchas about 3.5 cm, 3 cm. or less. In a preferred embodiment, the devicehas a dimension in at least one of these directions that is less than 3cm.

In some embodiments, the device may have a different dimension in atleast two of the three directions, and in some cases in each of thethree directions, so that the device is non-uniform in shape. Due to thenon-uniform shape, the device may be able to achieve an orientation ofreduced compression in the empty bladder, which also is non-uniform inshape. In other words, there may be a particular orientation for thedevice in the empty bladder that allows the device to exert less contactpressure against the bladder wall, making the device more tolerable forthe patient.

The overall shape of the device may enable the device to reorient itselfwithin the bladder to reduce its engagement or contact with the bladderwall. For example, the overall exterior shape of the device may becurved, and all or a majority of the exterior or exposed surfaces of thedevice may be substantially rounded. The device also may besubstantially devoid of sharp edges, and is exterior surfaces may beformed from a material that experiences reduced frictional engagementwith the bladder wall. Such a configuration may enable the device toreposition itself within the empty bladder so that the device applieslower contact pressures to the bladder wall. In other words, the devicemay slip or roll against the bladder wall into a lower energy position,meaning a position in which the device experiences less compression.

An example of a device that generally satisfies these characteristics isshown in FIG. 1, and examples of specific device configurations thatsatisfy these characteristics are described below with reference toExample 1 and Example 3. In particular, the illustrated device isgenerally planar in shape even though the device occupiesthree-dimensional space. Such a device may define a minor axis, aboutwhich the device is substantially symmetrical, and a major axis that issubstantially perpendicular to the minor axis. The device may have amaximum dimension in the direction of the major axis that does notexceed about 6 cm, and in particular embodiments is less than 5 cm, suchas about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm, or smaller. Thedevice may have a maximum dimension in the direction of the minor axisthat does not exceed about 4.5 cm, and in particular embodiments is lessthan 4 cm, such as about 3.5 cm, about 3 cm, or smaller. The device iscurved about substantially its entire exterior perimeter in both a majorcross-sectional plane and a minor cross-sectional plane. In other words,the overall exterior shape of the device is curved and thecross-sectional shape of the device is rounded. Thus, the device issubstantially devoid of edges, except for edges on the two flat ends,which are completely protected within the interior of the device whenthe device lies in a plane. These characteristics enable the device toreorient itself into a position of reduced compression when in the emptybladder.

Such devices may exhibit certain behaviors when subjected to acompression test, wherein the device is compressed between two platensand the compressive load is captured as a function of the distancebetween the two platens. The distance between the platens corresponds tothe dimension of the device in the direction of the compressive load. Anexample of such a compression test is described below with reference toExample 8, which shows that the devices described below in Example 1 andExample 3 can be compressed to a dimension of about 3 cm with an actingforce of about 1 N or less. These devices were found to be tolerablewithin the bladder, as described below with reference to Examples 4, 5,6, and 7. Thus, devices may be tolerable if compressible to a maximumdimension in any direction of about 3 cm with an acting force of about 1N or less. In some cases, a device may be tolerable if the device can becompressed to a maximum dimension in any direction of about 3 cm with anacting force of about 0.5 N, about 0.2 N, about 0.1 N, about 0.01 N, orless. In such cases, it is thought that the pressure exerted on thebladder by the device may be below those ranges that result in anurgency of urination or a sensation of bladder fullness. By way ofexample, the device described below with reference to Example 1 wascalculated to exert a pressure on the bladder wall of about 770 Pa whencompressed to a maximum dimension of 3 cm, which may be below thepressure at which a sensation of fullness first emerges. Similarly, thedevice described below with reference to Example 3 was calculated toexert a pressure on the bladder wall of about 2.7 kPa when compressed toa maximum distance of 3 cm, which may be comfortably noticeable to thepatient.

The device also may be small enough in the retention shape to permitintravesical mobility. In particular, the device when deployed may besmall enough to move within the bladder, such as to move freely orunimpeded throughout the entire bladder under most conditions of bladderfullness, facilitating patient tolerance of the device. Free movement ofthe device also facilitates uniform drug delivery throughout the entirebladder, as opposed to a particular bladder location located near therelease orifice. However, devices that otherwise move freely within thebladder may be impeded from moving freely when the bladder is completelyempty, and yet the device may still be tolerable if sufficientlycompressible as described above.

The device also may have a density that is selected to facilitatefloatation. The device has a minimum density in a dry and unloadedstate, meaning the device is not loaded with drug and fluid is notpresent in the device walls or lumens. Example 2 below describes adevice in such an unloaded or placebo configuration. The density of thedevice increases when the device is loaded with drug. Example 1 andExample 3 below describe devices in such loaded or activeconfigurations. The density of the device also increases when the deviceis in a wet state, meaning fluid is present in the device walls andlumens. The device enters the wet state upon implantation in thebladder, as the device becomes surrounded by urine. In use, the devicemay have a maximum density after implantation, when the device is loadedwith the maximum drug payload and liquid displaces any air present inthe walls and lumens. Subsequently, the density of the device may remainessentially the same or decrease as the drug is solubilized andreleased, and replaced by urine.

In general, the device in the dry and loaded state may have a density inthe range of about 0.5 g/mL to about 1.5 g/mL, such as between about 0.7g/mL to about 1.3 g/mL. In some embodiments, the device in the dry andloaded has a density that is less than the density of water, such as adensity that is less than about 1 g/mL. Such densities facilitatebuoyancy and movement in the bladder. Lighter or lower density materialsmay be integrated into the device as needed to compensate for any higherdensity drug or other payload in the device, thereby maintaining anoverall density that facilitates buoyancy for tolerance purposes. Inaddition, air or another gas may be trapped in portions of the device toreduce the overall density. For example, the walls of retention framelumen may be made impermeable to water such that an air pocket is formedin the retention frame lumen about the elastic wire. A coating or sheathmay be applied to the walls, on either the inside or outside, to reducethe water permeability.

One example device may have a mass of about 0.40 grams or less and adensity of about 0.7 g/mL or less when unloaded. The device may beloaded with a drug having a mass of about 275 mg or less. In suchembodiments, the device when loaded may have a mass of about 0.675 gramsor less and a density of about 1.1 g/mL or less. Such a device may bewell tolerated in the bladder. Devices of smaller masses and densitieswould likewise be well tolerated.

The exact configuration and shape of the intravesical drug deliverydevice may be selected depending upon a variety of factors including thespecific site of deployment/implantation, route of implantation, drug,dosage regimen, and therapeutic application of the device. The design ofthe device may minimize the patient's pain and discomfort, while locallydelivering a therapeutically effective dose of the drug to a tissue site(e.g., urothelial tissue) in a patient.

The implantable drug delivery device can be made to be completely orpartially bioerodible so that no explantation, or retrieval, of thedevice is required following release of the drug formulation. As usedherein, the term “bioerodible” means that the device, or part thereof,degrades in vivo by dissolution, enzymatic hydrolysis, erosion,resorption, or a combination thereof. In one embodiment, thisdegradation occurs at a time that does not interfere with the intendedkinetics of release of the drug from the device. For example,substantial erosion of the device may not occur until after the drugformulation is substantially or completely released. In anotherembodiment, the device is erodible and the release of the drugformulation is controlled at least in part by the degradation or erosioncharacteristics of the erodible device body.

Alternatively, the implantable drug delivery device may be at leastpartially non-bioerodible. In some embodiments, the device is formedfrom materials suited for urological applications, such as medical gradesilicone, natural latex, PTFE, ePTFE, PLGA, PGS, stainless steel,nitinol, elgiloy (non ferro magnetic metal alloy), polypropylene,polyethylene, polycarbonate, polyester, nylon, or combinations thereof.Following release of the drug formulation, the device and/or theretention frame may be removed substantially intact or in multiplepieces. In some embodiments, the device is partially bioerodible so thatthe device, upon partial erosion, breaks into non-erodible pieces smallenough to be excreted from the bladder. Useful biocompatible erodibleand non-erodible materials of construction are known in the art.

In a preferred embodiment, the drug delivery device is sterilized, suchas after the device is manufactured/assembled and before the device isimplanted. In some cases, the device may be sterilized after the deviceis packaged, such as by subjecting the package to gamma irradiation orethylene oxide gas.

The Drug Reservoir Portion

In one embodiment, the drug reservoir portion of the device includes anelongated tube. An interior of the tube may define one or more drugreservoirs, and a drug formulation may be housed in the drugreservoir(s). In another embodiment, the drug reservoir portion is in aform other than a tube.

The release rate of the drug from the drug reservoir portion generallyis controlled by the design of the combination of the device components,including but not limited to the materials, dimensions, surface area,and apertures of the drug reservoir portion, as well as the particulardrug formulation and total mass of drug load, among others.

An example of such a drug reservoir portion is shown in FIGS. 1-3. Asshown, the drug reservoir portion 102 may include a body formed from anelastomeric tube 122. The tube 122 defines a reservoir 108 that containsa number of drug tablets 112. Ends of the tube 122 may be sealed withsealing structures 120. At least one aperture 118 may be disposed in thetube 122. In cases in which an aperture 118 is provided, the aperture118 may be closed by a degradable timing membrane, which may control theinitiation of release of the drug formulation from the reservoir. Insome cases, a sheath or coating may be positioned about at least aportion of the tube 122 to control or reduce the release rate, such asby reducing the osmotic surface area of the tube or by reducingdiffusion through the tube wall. For simplicity, the degradable timingmembranes and sheaths or coatings are not shown.

In one embodiment, the drug reservoir portion operates as an osmoticpump. In such embodiments, the tube may be formed from a water permeablematerial, such as a silicone, or tube may have a porous structure, orboth. Following implantation, water or urine permeates through the wallof the tube, one or more apertures formed through the tube, or one ormore passing pores formed through a porous tube. The water enters thereservoir, and is imbibed by the drug formulation. Solubilized drug isdispensed at a controlled rate out of the reservoir through the one ormore apertures, driven by osmotic pressure in the reservoir. Thedelivery rate and overall performance of the osmotic pump is affected bydevice parameters, such as the surface area of the tube; thepermeability to liquid of the material used to form the tube; the shape,size, number and placement of the apertures; and the drug formulationdissolution profile, among other factors. The delivery rate can bepredicted from the physicochemical parameters defining the particulardrug delivery system, according to well known principles, which aredescribed, for example, in Theeuwes, J. Pharm. Sci., 64(12):1987-91(1975). In some embodiments, the device may initially exhibit azero-order release rate and subsequently may exhibit a reduced,non-zero-order release rate, in which case the overall drug releaseprofile may be determined by the initial zero-order release rate and thetotal payload. Representative examples of osmotic pump designs, andequations for selecting such designs, are described in U.S. PatentPublication No. 2009/0149833.

In an alternative embodiment, the device may operate essentially bydiffusion of the drug from the tube through (i) one or more discreteapertures formed in the wall of the tube, or passing pores formed in thewall of a porous tube, or (ii) through the wall of the tube itself,which may be permeable to the drug, or (iii) a combination thereof. Inembodiments in which diffusion occurs through the wall, the apertures orpassing pores may not be included. In still other embodiments, thedevice may operate by a combination of osmosis and diffusion.

The drug reservoir portion may be formed from an elastomeric material,which may permit elastically deforming the device for its insertion intoa patient, e.g., during its deployment through deployment instrumentsuch as a cystoscope or catheter. For example, the tube may beelastically deformed along with the retention frame for intravesicalimplantation, as described in further detail below.

In preferred embodiments, the drug reservoir portion is formed from amaterial that is both elastomeric and water permeable. One material thatis both elastomeric and water permeable is silicone, although otherbiocompatible materials may be used.

The length, diameter, and thickness of the tube may be selected based onthe volume of drug formulation to be contained, the desired rate ofdelivery of the drug from the tube, the intended site of implantation ofthe device within the body, the desired mechanical integrity for thedevice, the desired release rate or permeability to water and urine, thedesired induction time before onset of initial release, and the desiredmethod or route of insertion into the body, among others. The tube wallthickness may be determined based on the mechanical properties and waterpermeability of the tube material, as a tube wall that is too thin maynot have sufficient mechanical integrity while a tube wall that is toothick may experience an undesirably long induction time for initial drugrelease from the device.

In one embodiment, the device body is non-resorbable. It may be formedof a medical grade silicone tubing, as known in the art. Other examplesof suitable non-resorbable materials include synthetic polymers selectedfrom poly(ethers), poly(acrylates), poly(methacrylates), poly(vinylpyrolidones), poly(vinyl acetates), poly(urethanes), celluloses,cellulose acetates, poly(siloxanes), poly(ethylene),poly(tetrafluoroethylene) and other fluorinated polymers,poly(siloxanes), copolymers thereof, and combinations thereof.

In some embodiments, the device body is bioerodible. In one embodimentof a bioerodible device, the tube of the body is formed of abiodegradable or bioresorbable polymer. Examples of suitable suchmaterials include synthetic polymers selected from poly(amides),poly(esters), poly(ester amides), poly(anhydrides), poly(orthoesters),polyphosphazenes, pseudo poly(amino acids),poly(glycerol-sebacate)(PGS), copolymers thereof, and mixtures thereof.In a preferred embodiment, the resorbable synthetic polymers areselected from poly(lactic acids), poly(glycolic acids),poly(lactic-co-glycolic acids), poly(caprolactones), and mixturesthereof. Other curable bioresorbable elastomers includepoly(caprolactone) (PC) derivatives, amino alcohol-based poly(esteramides) (PEA) and poly (octane-diol citrate) (POC). PC-based polymersmay require additional cross-linking agents such as lysine diisocyanateor 2,2-bis(ϵ-caprolacton-4-yl)propane to obtain elastomeric properties.

The tube of a drug reservoir portion tube may be substantially linearand in some cases may be substantially cylindrical with a circularcross-section, although square, triangle, hexagon, and other polygonalcross-sectional shapes can be used, among others.

The ends of the tube may be sealed to limit escape of the drug, such aswith a sealing structure or other sealing means. The sealing structuremay have any shape suited to plug or close the tube end, such as acylinder 120 as shown in FIG. 1, a ball, a disk, or others. In someembodiments, the sealing structure may have a larger diameter than theinner diameter of the tube, such that the tube stretches to fit snuglyabout the sealing structure, closing the tube and retaining the sealingstructure in place. The sealing structure may be formed frombiocompatible material, including a metal such as stainless steel, apolymer such as silicone, a ceramic, sapphire, or adhesive, among othersor combinations thereof. The material may be biodegradable orbioerodible. A medical grade silicone adhesive or other adhesive alsomay be loaded into the tube in a workable form and may then cure withinthe tube to seal the end.

In some embodiments, the tube may have multiple reservoirs. Eachreservoir may be defined by a portion of the tube inner surface and atleast one partition. The partition may be a partition structure or pluginserted into the tube, such as a cylinder, sphere, or disk, amongothers, in which case the partition structure may have a largercross-section than the tube, securing the partition structure in placeand segregating adjacent reservoirs. For example, the cylindrical plug120 of FIG. 1 that closes the tube end may instead serve as a partitionstructure to segregate two reservoirs positioned adjacent to each otheralong the length of the tube. The partition may be non-porous orsemi-porous, non-resorbable or resorbable and may be formed of amaterial described above with reference to the cylindrical plug 120. Thepartition also may be formed in the tube, such as by molding. Forexample, one or more webs may extend through the tube along its lengthto segregate axial reservoirs that extend along the length of the tube,as shown in Examples J through L of FIG. 6. The partition also may be astructure that joins two different tubes that serve as separatereservoirs, as shown in Examples M through O of FIG. 6.

The multiple reservoirs permit segregating two or more different drugformulations in different reservoirs, delivering a single drug fromdifferent reservoirs at different rates or times following implantation,or combinations thereof. For example, two different reservoirs may havedifferent configurations, such as different materials, differentpermeabilities, different numbers or placements of apertures (or theabsence of apertures), different timing membranes in the apertures,among others or combinations thereof. The two different reservoirs alsomay house the same or different drug formulations in the same ordifferent forms (such as liquid, semi-solid, and solid), or combinationsthereof. The two different reservoirs further may be configured torelease drug via different release mechanisms, such as via osmosisthrough an aperture and by diffusion through a drug reservoir wall thatmay lack an aperture completely. Coatings or sheaths also may beprovided along different portions of a single drug reservoir or alongdifferent drug reservoirs housing the same or different drugformulations. These embodiments can be combined and varied to achievethe desired release profile of the desired drug.

For example, the onset of release of two doses in different reservoirscan be staged by configuring the device accordingly, such as by usingdifferent materials for portions of the tube defining differentreservoirs, by associating the aperture(s) of different reservoirs withdifferent timing membranes, by placing drugs with different solubilitiesin the reservoirs, or by placing drugs with different forms in thereservoirs, such as a liquid form for immediate release and a solid formto be solubilized prior to release. Thus, the device may release somedrug relatively quickly after implantation while other drug mayexperience an induction time before beginning release.

In one embodiment, the total volume of the reservoir (or combinedreservoirs) is sufficient to contain all the drug needed for localdelivery over the course of a single treatment, reducing the number ofprocedures needed to treat a particular condition.

Apertures

In some embodiments, the device includes one or more apertures ororifices for dispensing the drug, such as via osmosis, diffusion, or acombination thereof, among other. The apertures may be spaced along thetube to provide a passageway for release of the drug formulation. Theapertures or orifices may be positioned through a sidewall or an end ofthe tube. The apertures may be in fluid communication with one or morereservoirs. An embodiment of an aperture 118 is shown on the drugreservoir portion in FIGS. 1 and 3.

The aperture may be located about a middle of the drug reservoir portionor adjacent to its exit, which may affect the ease of loading solid drugunits into the drug reservoir portion as described below. The aperturesmay be positioned away from a portion of the tube that will be foldedduring insertion to limit tearing of degradable membranes on theapertures.

In embodiments in which the device includes a device body that definesboth drug reservoir and retention frame lumens, such as the embodimentshown in FIG. 3, the aperture or apertures may have various positions onthe wall of the drug reservoir lumen with reference to the wall of theretention frame lumen, as further described below.

The size, number, and placement of the apertures may be selected toprovide a controlled rate of release of the drug. A device that operatesprimarily as an osmotic pump may have one or more apertures sized smallenough to reduce diffusion of the drug through the aperture(s), yetlarge enough and spaced appropriately along the tube to reduce thebuildup of hydrostatic pressure in the tube. Within these constraints,the size and number of apertures for a single device (or reservoir) canbe varied to achieve a selected release rate. In exemplary embodiments,the diameter of the aperture is between about 20 μm and about 500 μm,such as between about 25 μm and about 300 μm, and more particularlybetween about 30 μm and about 200 μm. In one particular example, theaperture has a diameter between about 100 μm and about 200 μm, such asabout 150 μm. In embodiments where the device operates primarily bydiffusion, the apertures may be in this range or larger. A single devicemay have apertures of two or more different sizes. The aperture may becircular, although other shapes are possible and envisioned, with theshape typically depending on manufacturing considerations. Examples ofprocesses for forming the apertures include mechanical punching, laserdrilling, laser ablation, and molding. The aperture may slightly taperfrom an exterior to an interior of the tube, and the aperture may becreated either before or after the drug is loaded into the tube. Theaperture also may be formed in an orifice structure disposed in an endof the tube, such as a ruby or sapphire precision orifice structurefrom, for example, Bird Precision Orifices, Swiss Jewel Company.

In some embodiments, the drug reservoir portion may not have anyapertures, in which case the drug may be released via a releasemechanism other than osmosis, such as diffusion through the wall of thedrug reservoir portion. Similarly, a drug reservoir portion havingmultiple discrete drug reservoirs may have apertures associated withall, some, or none of the drug reservoirs, in which cases release fromthe different drug reservoirs may occur via different releasemechanisms.

Degradable Membranes

In one embodiment, a degradable membrane, i.e., a timing membrane, isdisposed over or in the apertures (e.g., in register with the aperture)to control the onset of release of the drug formulation. The degradablemembrane may be a coating over all or some of the outer surface of thetube or a discrete membrane above or within the aperture. Two or moredegradable membranes also may be used to control release from oneaperture. The membranes may be formed, for example, of a resorbablesynthetic polymer (such as polyester, a poly(anhydride), or apolycaprolactone) or a resorbable biological material (such ascholesterol, other lipids and fats). Additional details are described inU.S. Publication No. 2009/0149833.

The Drug Formulation and Solid Drug Tablets

The drug formulation can include essentially any therapeutic,prophylactic, or diagnostic agent, such as one that would be useful todeliver locally to a body cavity or lumen or regionally about the bodycavity or lumen. The drug formulation may consist only of the drug, orone or more pharmaceutically acceptable excipients may be included. Thedrug may be a biologic. The drug may be a metabolite. As used herein,the term “drug” with reference to any specific drug described hereinincludes its alternative forms, such as salt forms, free acid forms,free base forms, and hydrates. Pharmaceutically acceptable excipientsare known in the art and may include lubricants, viscosity modifiers,surface active agents, osmotic agents, diluents, and other non-activeingredients of the formulation intended to facilitate handling,stability, dispersibility, wettability, and/or release kinetics of thedrug.

In a preferred embodiment, the drug formulation is in a solid orsemi-solid form in order to reduce the overall volume of the drugformulation and thereby reduce the size of the device, facilitatingimplantation. The semi-solid form may be, for example, an emulsion orsuspension; a gel or a paste. In many embodiments, the drug formulationdesirably includes no or a minimum quantity of excipient for the samereasons of volume/size minimization.

In some embodiments, the drug is a high solubility drug. As used herein,the term “high solubility” refers to a drug having a solubility aboveabout 10 mg/mL water at 37° C. In other embodiments, the drug is a lowsolubility drug. As used herein, the term “low solubility” refers to adrug having a solubility from about 0.01 mg/mL to about 10 mg/mL waterat 37° C. The solubility of the drug may be affected at least in part byits form. For example, a drug in the form of a water soluble salt mayhave a high solubility, while the same drug in base form may have a lowsolubility. One example is lidocaine, which has a high solubility ofabout 680 mg/mL when in the form of a lidocaine hydrochloridemonohydrate, a water-soluble salt, but has a low solubility of about 8mg/mL when in the form of lidocaine base. High solubility drugs may besuited for release due to an osmotic pressure gradient, such as via oneor more apertures or passing pores through the device wall, while lowsolubility drugs may be suited for release via diffusion, such asdirectly through the device wall or through one or more apertures orpassing pores in the device wall. For example, lidocaine base maydiffuse directly through a thin silicone wall, while lidocainehydrochloride may not. Thus, the drug may be formulated to have a highor low solubility depending on the intended release mode. In oneembodiment, the drug is formulated to improve its apparent solubility inthe implantation environment, such as its apparent solubility in urinewithin the bladder.

In a particular embodiment, the devices provide pain relief to thepatient. A variety of anesthetic agents, analgesic agents, andcombinations thereof may be used. In embodiments, the device deliversone or more local anesthetic agents. The local anesthetic agent may be acocaine analogue. In particular embodiments, the local anesthetic agentis an aminoamide, an aminoester, or combinations thereof. Representativeexamples of aminoamides or amide-class anesthetics include articaine,bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine,lidocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.Representative examples of aminoesters or ester-class anestheticsinclude amylocaine, benzocaine, butacaine, chloroprocaine, cocaine,cyclomethycaine, dimethocaine, hexylcaine, larocaine, meprylcaine,metabutoxycaine, orthocaine, piperocaine, procaine, proparacaine,propoxycaine, proxymetacaine, risocaine, and tetracaine. These localanesthetics typically are weak bases and may be formulated as a salt,such as a hydrochloride salt, to render them water-soluble, although theanesthetics also can be used in free base or hydrate form. Otheranesthetics, such as lontocaine, also may be used. The drug also can bean antimuscarinic compound that exhibits an anesthetic effect, such asoxybutynin or propiverine. The drug also may include other drugsdescribed herein, alone or in combination with a local anesthetic agent.

In certain embodiments, the analgesic agent includes an opioid.Representative examples of opioid agonists include alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, proheptazine, promedol,properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol,pharmaceutically acceptable salts thereof, and mixtures thereof. Otheropioid drugs, such as mu, kappa, delta, and nociception opioid receptoragonists, are contemplated.

Representative examples of other suitable pain relieving agents includesuch agents as salicyl alcohol, phenazopyridine hydrochloride,acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen,indomethacin, naproxen.

In certain embodiments, the drug delivery device is used to treatinflammatory conditions such as interstitial cystitis, radiationcystitis, painful bladder syndrome, prostatitis, urethritis,post-surgical pain, and kidney stones. Non-limiting examples of specificdrugs for these conditions include lidocaine, glycosaminoglycans (e.g.,chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS),dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate,ketorolac, or a combination thereof. For kidney stones, the drug(s) maybe selected to treat pain and/or to promote dissolution of renal stones.

Other non-limiting examples of drugs that may be used in the treatmentof IC include nerve growth factor monoclonal antibody (MAB) antagonists,such as Tanezumab, and calcium channel alpha-2-delta modulators, such asPD-299685 or gabepentin. Evidence suggests that the bladder expressesnerve growth factor (NGF) locally, since exogenously delivered NGF intothe bladder induces bladder hyperactivity and increases the excitabilityof dissociated bladder afferent neurons (Nature Rev Neurosci 2008;9:453-66). Accordingly, it would be advantageous to locally deliver aMAB or other agent against NGF using the described delivery devices,significantly reducing the total dose needed for therapeutic efficacy.Evidence also suggests that binding of the alpha-2-delta unit ofvoltage-sensitive calcium channels, such as with gabapentin, may beeffective in the treatment of diseases of neuropathic pain such asfibromyalgia and that there may be common mechanisms between IC anddiseases of neuropathic pain (See Tech Urol. 2001 Mar. 7(1):47-49).Accordingly, it would be advantageous to locally deliver a calciumchannel alpha-2-delta modulator, such as PD-299685 or gabepentin, usingthe described delivery devices, minimizing does-related systemictoxicities in the treatment of IC.

Other intravesical cancer treatments include small molecules, such asApaziquone, adriamycin, AD-32, doxorubicin, doxetaxel, epirubicin,gemcitabine, HTI-286 (hemiasterlin analogue), idarubicin, γ-linolenicacid, mitozantrone, meglumine, and thiotepa; large molecules, such asActivated macrophages, activated T cells, EGF-dextran, HPC-doxorubicin,IL-12, IFN-a2b, IFN-γ, α-lactalbumin, p53 adenovector, TNFα;combinations, such as Epirubicin+BCG, IFN+farmarubicin, Doxorubicin+5-FU(oral), BCG+IFN, and Pertussis toxin+cystectomy; activated cells, suchas macrophages and T cells; intravesical infusions such as IL-2 andDoxorubicin; chemo sensitizers, such as BCG+antifirinolytics(paramethylbenzoic acid or aminocaproic acid) and Doxorubicin+verapimil;diagnostic/imaging agents, such as Hexylaminolevulinate,5-aminolevulinic acid, Iododexyuridine, HMFG1 Mab+Tc99m; and agents forthe management of local toxicity, such as Formaline (hemorrhagiccystitis).

In one particular embodiment, the drug delivery device is used inassociation with the placement of a ureteral stent, such as to treatpain, urinary urgency or urinary frequency resulting from ureteral stentplacement. Non-limiting examples of specific drugs for such treatmentinclude anti-muscarinics, α-blockers, narcotics, and phenazopyridine,among others.

The drug delivery device can be used, for example, to treat urinaryincontinence, frequency, or urgency, including urge incontinence andneurogenic incontinence, as well as trigonitis. Drugs that may be usedinclude anticholinergic agents, antispasmodic agents, anti-muscarinicagents, β-2 agonists, alpha adrenergics, anticonvulsants, norepinephrineuptake inhibitors, serotonin uptake inhibitors, calcium channelblockers, potassium channel openers, and muscle relaxants.Representative examples of suitable drugs for the treatment ofincontinence include oxybutynin, S-oxybutytin, emepronium, verapamil,imipramine, flavoxate, atropine, propantheline, tolterodine, rociverine,clenbuterol, darifenacin, terodiline, trospium, hyoscyamin, propiverine,desmopressin, vamicamide, clidinium bromide, dicyclomine HCl,glycopyrrolate aminoalcohol ester, ipratropium bromide, mepenzolatebromide, methscopolamine bromide, scopolamine hydrobromide, iotropiumbromide, fesoterodine fumarate, YM-46303 (Yamanouchi Co., Japan),lanperisone (Nippon Kayaku Co., Japan), inaperisone, NS-21 (NipponShinyaku Orion, Formenti, Japan/Italy), NC-1800 (Nippon Chemiphar Co.,Japan), ZD-6169 (Zeneca Co., United Kingdom), and stilonium iodide.

In another embodiment, the drug delivery device is used to treat urinarytract cancer, such as bladder cancer and prostate cancer. Drugs that maybe used include antiproliferative agents, cytotoxic agents,chemotherapeutic agents, or a combination thereof. Representativeexamples of drugs which may be suitable for the treatment of urinarytract cancer include Bacillus Calmette Guerin (BCG) vaccine, cisplatin,doxorubicin, valrubicin, gemcitabine, mycobacterial cell wall-DNAcomplex (MCC), methotrexate, vinblastine, thiotepa, mitomycin,fluorouracil, leuprolide, diethylstilbestrol, estramustine, megestrolacetate, cyproterone, flutamide, a selective estrogen receptormodulators (i.e. a SERM, such as tamoxifen), botulinum toxins, andcyclophosphamide. The drug may be a biologic, and it may comprise amonoclonal antibody, a TNF inhibitor, an anti-leukin, or the like. Thedrug also may be an immunomodulator, such as a TLR agonist, includingimiquimod or another TLR7 agonist. The drug also may be a kinaseinhibitor, such as a fibroblast growth factor receptor-3(FGFR3)-selective tyrosine kinase inhibitor, a phosphatidylinositol 3kinase (PI3K) inhibitor, or a mitogen-activated protein kinase (MAPK)inhibitor, among others or combinations thereof. Other examples includecelecoxib, erolotinib, gefitinib, paclitaxel, polyphenon E, valrubicin,neocarzinostatin, apaziquone, Belinostat, Ingenol mebutate, Urocidin(MCC), Proxinium (VB 4845), BC 819 (BioCancell Therapeutics), Keyholelimpet haemocyanin, LOR 2040 (Lorus Therapeutics), urocanic acid, OGX427 (OncoGenex), and SCH 721015 (Schering-Plough). The drug treatmentmay be coupled with a conventional radiation or surgical therapytargeted to the cancerous tissue.

In still another embodiment, the present intravesical drug deliverydevice is used to treat infections involving the bladder, the prostate,and the urethra. Antibiotics, antibacterial, antifungal, antiprotozoal,antiseptic, antiviral and other antiinfective agents can be administeredfor treatment of such infections. Representative examples of drugs forthe treatment of infections include mitomycin, ciprofloxacin,norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin,amoxicillin, nafcillin, trimethoprim, sulfonamidestrimethoprimsulfamethoxazole, erythromycin, doxycycline, metronidazole,tetracycline, kanamycin, penicillins, cephalosporins, andaminoglycosides.

In other embodiments, the present drug delivery device is used to treatfibrosis of a genitourinary site, such as the bladder or uterus.Representative examples of drugs for the treatment of fibroids includepentoxphylline (xanthine analogue), antiTNF, antiTGF agents, GnRHanalogues, exogenous progestins, antiprogestins, selective estrogenreceptor modulators, danazol and NSAIDs.

The implantable drug delivery device also may be used to treatneurogenic bladder. Representative examples of drugs for the treatmentof neurogenic bladder include analgesics or anaesthetics, such aslidocaine, bupivacaine, mepivacaine, prilocaine, articaine, andropivacaine; anticholinergics; antimuscarinics such as oxybutynin orpropiverine; a vanilloid, such as capsaicin or resiniferatoxin;antimuscarinics such as ones that act on the M3 muscarinic acetylcholinereceptor (mAChRs); antispasmodics including GABA_(B) agonists such asbaclofen; botulinum toxins; capsaicins; alpha-adrenergic antagonists;anticonvulsants; serotonin reuptake inhibitors such as amitriptyline;and nerve growth factor antagonists. In various embodiments, the drugmay be one that acts on bladder afferents or one that acts on theefferent cholinergic transmission, as described in Reitz et al., SpinalCord 42:267-72 (2004).

The possible drug useful for treatment of neurogenic bladder may becategorized into one of two general types: those for treating spasticneurogenic bladder and those for treating flaccid neurogenic bladder. Inone embodiment, the drug is selected from those known for the treatmentof incontinence due to neurologic detrusor overactivity and/or lowcompliant detrusor. Examples of these types of drugs include bladderrelaxant drugs (e.g., oxybutynin (antimuscarinic agent with a pronouncedmuscle relaxant activity and local anesthetic activity), propiverine,impratroprium, tiotropium, trospium, terodiline, tolterodine,propantheline, oxyphencyclimine, flavoxate, and tricyclicantidepressants; drugs for blocking nerves innervating the bladder andurethra (e.g., vanilloids (capsaicin, resiniferatoxin), botulinum-Atoxin); or drugs that modulate detrusor contraction strength,micturition reflex, detrusor sphincter dyssynergia (e.g., GABAb agonists(baclofen), benzodiazapines). In another embodiment, the drug isselected from those known for the treatment of incontinence due toneurologic sphincter deficiency. Examples of these drugs include alphaadrenergic agonists, estrogens, beta-adrenergic agonists, tricyclicantidepressants (imipramine, amitriptyline). In still anotherembodiment, the drug is selected from those known for facilitatingbladder emptying (e.g., alpha adrenergic antagonists (phentolamine) orcholinergics). In yet another embodiment, the drug is selected fromamong anticholinergic drugs (e.g., dicyclomine), calcium channelblockers (e.g., verapamil) tropane alkaloids (e.g., atropine,scopolamine), nociceptin/orphanin FQ, and bethanechol (e.g., m3muscarinic agonist, choline ester).

The excipient of the drug formulation may be a matrix material, selectedto modulate or control the rate of release of the drug from thereservoir. In one embodiment, the matrix material may be a resorbable ornon-resorbable polymer. In another embodiment, the excipient comprises ahydrophobic or amphiphilic compound, such as a lipid (e.g., a fattyacids and derivatives, mono-, di- and triglycerides, phospholipids,sphingolipids, cholesterol and steroid derivatives, oils, vitamins andterpenes). The drug formulation may provide a temporally modulatedrelease profile or a more continuous or consistent release profile.Other drugs and excipients may be used for other therapies.

In some embodiments, the drug formulation is in solid form. For example,the drug formulation is formed into solid drug units that are loadedinto the drug reservoir portion. Each of the drug units is a solid,discrete object that substantially retains a selectively imparted shape(at the temperature and pressure conditions to which the delivery devicenormally will be exposed during assembly, storage, and handling beforeimplantation). The drug units may be in the form of tablets, pellets, orbeads, although other configurations are possible. For example, FIGS. 1and 2 illustrate a number of the solid drug units 112 that are suitedfor implantation loaded into the drug reservoir lumen 108 of the drugdelivery device 100.

The drug tablets made by a direct compression tableting process, amolding process, or other processes known in the pharmaceutical arts.The tablets optionally may be coated with one or more materials known inthe art for protecting the tablets against destructive exposure tooxygen or humidity during tablet handling, device assembly and storage;for facilitating device loading; for aesthetics; or for facilitating,retarding, or otherwise controlling in vivo dissolution and drug releasecharacteristics. The drug formulation also may be loaded into the drugreservoir in workable form and may cure therein. Thereafter, thesolidified drug may be broken along the length of the drug reservoir toform the interstices or breaks that permit device deformation. Forexample, in embodiments in which the drug formulation is configured tobe melted and solidified, the drug formulation can be melted, injectedinto the drug reservoir in melted form, solidified in the drugreservoir, and broken into pieces in the drug reservoir to accommodatedevice deformation or movement. The drug formulation also may beextruded with the drug reservoir, may cure within the drug reservoir,and subsequently may be broken along the length of the reservoir toaccommodate device deformation.

The drug tablet includes a drug content and may include an excipientcontent. The drug content includes one or more drugs or activepharmaceutical ingredients (API), while the excipient content includesone or more excipients. The term “excipient” is known in the art, andrepresentative examples of excipients useful in the present drug tabletsmay include ingredients such as binders, lubricants, glidants,disintegrants, colors, fillers or diluents, coatings and preservatives,as well as other ingredients to facilitate manufacturing, storing, oradministering the drug tablet.

In order to maximize the amount of drug that can be stored in andreleased from a given drug delivery device of a selected (small) size,the drug tablet preferably comprises a high weight fraction of drug orAPI, with a reduced or low weight fraction of excipients as are requiredfor tablet manufacturing and device assembly and use considerations. Forthe purposes of this disclosure, terms such as “weight fraction,”“weight percentage,” and “percentage by weight” with reference to drug,or API, refers to the drug or API in the form employed, such as in saltform, free acid form, free base form, or hydrate form. For example, adrug tablet that has 90% by weight of a drug in salt form may includeless than 90% by weight of that drug in free base form.

In one embodiment, the drug tablet is more than 50% by weight drug. In apreferred embodiment, 75% or more of the weight of the drug tablet isdrug, with the remainder of the weight comprising excipients, such aslubricants and binders that facilitate making the drug tablet. For thepurposes of this disclosure, the term “high weight fraction” withreference to the drug or API means that excipients constitute less than25 wt %, preferably less than 20 wt %, more preferably less than 15 wt%, and even more preferably less than 10 wt % of the drug tablet. Insome cases, the drug content comprises about 75% or more of the weightof the drug tablet. More particularly, the drug content may compriseabout 80% or more of the weight of the drug tablet. For example, thedrug content may comprise between about 85% and about 99.9% of theweight of the drug tablet. In some embodiments, the excipient contentcan be omitted completely.

In one embodiment, the drug and excipients are selected and the tabletformulated to be water soluble, so that the drug tablets can besolubilized when the device is located within the vesical, to releasethe solubilized drug. In a preferred embodiment, the drug tablets areformulated to be sterilizable, either within or outside of the drugdelivery device, without substantial or detrimental changes in thechemical or physical composition of the drug tablets. Such drug tabletsmay be quite different from conventional drug tablets, which typicallyinclude active ingredients that constitute less than 50% of the drugtablet content by weight, with the remainder of the drug tabletcomprising excipients that are often insoluble and/or may not be suitedfor conventional sterilization. Furthermore, the present drug tabletsmay be sized and shaped for use with an implantable drug deliverydevice. For example, the drug tablets may be “mini-tablets” that aremuch smaller in size than conventional tablets, which may permitinserting the drug tablets through a lumen such as the urethra into acavity such as the bladder. An embodiment of a solid drug tablet 112 forintravesical insertion or other in vivo implantation is shown in FIGS.1-3.

In embodiments in which one or more pharmaceutically acceptableexcipients are included, the excipients may facilitate loading the soliddrug units in the device. For example, the excipients may increase thelubricity of the drug units so that the drug units can slide withreference to the interior lumen walls of the drug reservoir portion. Theexcipients also may facilitate forming the therapeutic agent or agentsinto a solid drug tablet that can be loaded into the drug reservoirportion. The excipients also may affect the kinetics of drug releasefrom the device, such as by increasing or retarding the solubility ordissolution rate of the drug units. In some embodiments, however, thedrug release rate is predominately controlled by characteristics of thedrug reservoir, such as the tube thickness and permeability to water orurine, while the excipient content of the drug units is primarilyselected to permit reliable production of drug units that are solid andinclude a relatively high weight fraction of drug.

The individual drug units may have essentially any selected shape anddimension that fits within the device. In one embodiment, the drug unitsare sized and shaped such that the drug reservoir portion issubstantially filled by a select number of drug units. Each drug unitmay have a cross-sectional shape that substantially corresponds to across-sectional shape of the drug reservoir portion. For example, thedrug units 112 are substantially cylindrical in shape as shown in FIGS.1 and 3 for positioning in the substantially cylindrical drug reservoirlumen 108 shown in FIG. 1. Once loaded, the drug units 112 substantiallyfill the drug reservoir lumen 108, forming the drug reservoir portion102.

The drug units may have outer dimensions that are about the same as, areslightly less than, or slightly exceed inner dimensions of the drugreservoir portion. In embodiments in which the outer dimensions of thedrug units exceed the inner dimensions of the drug reservoir portion,the drug units may be loaded into the drug reservoir portion under aflow of pressurized gas that causes the drug reservoir portion to expandoutward so that the drug units travel through it. When the flow ofpressurized gas is removed, the drug reservoir portion may return tohold the drug units in selected axial positions. Using larger diameterdrug units may increase the payload and thus the amount of drug that canbe delivered from a drug delivery device of a given size. For example,the drug unit 112 shown in FIGS. 1-3 has an outer diameter that slightlyexceeds an inner diameter of the drug reservoir lumen 108 shown in FIG.3. Such drug units 112 may be loaded into the lumen 108 under a flow ofpressurized gas that radially expands the drug reservoir wall 122 sothat the drug units 112 may travel through the drug reservoir lumen 108in an axial direction, and when the flow of pressurized gas is removed,the wall 122 may return to retain the drug units 112 in selected axialpositions along the length of the lumen 108, as shown in FIG. 1. It isnoted that the drug units 112 are shown smaller than the lumen 108merely for the purpose of visually differentiating the two parts. Inembodiments in which the outer dimensions of the drug units are smallerthan the inner dimensions of the drug reservoir portion, the drug unitsmay have reduced contact with the drug reservoir portion. Therefore, thedrug units may be loaded using a flow of pressurized gas at relativelylower pressure, as the flow of pressurized gas may not need to overcomethe force of friction.

In embodiments, the drug units are shaped to align in a row when housedin the drug reservoir. Each drug unit has a cross-sectional shape thatcorresponds to the cross-sectional shape of the drug reservoir, and eachdrug unit may have end face shapes that correspond to the end faces ofadjacent drug units. Thus, once the drug tablets are loaded in the drugreservoir, the line or row of drug tablets may substantially fill thedrug reservoir with interstices or breaks formed between adjacent drugunits. The interstices or breaks accommodate deformation or movement ofthe device, such as during deployment, while permitting the individualdrug units to retain their solid form. Thus, the drug delivery devicemay be relatively flexible or deformable despite being loaded with asolid drug, as each drug unit may be permitted to move with reference toadjacent drug units.

An example is shown in FIGS. 1-3, which illustrates the drug unit 112having circular flat end faces and a cylindrical side wall. Thus, thedrug unit 112 can be aligned in a row with other drug units 112 forloading into the cylindrical drug reservoir lumen 108 as shown in FIGS.1 and 2. When so loaded, the drug units 112 substantially fill the drugreservoir lumen 108, with interstices or breaks 116 formed between themto accommodate deformation or movement. The flat end faces permitpiecewise flexibility of the device while limiting the volume or spacewithin the drug reservoir portion that is devoted to the interstices orbreaks 116. Thus, the device can be substantially filled with solid drugwhile retaining its flexibility. Loading the device with a number ofdrug tablets 112, such as drug tablets that are relatively uniform insize and shape, beneficially permits manufacturing a device that behavesas expected in response to expected forces during and after implantationand exhibits expected drug release characteristics once implanted. Thatis, the tablet uniformity advantageously enables reproducibility inproducing the medical product and thereby generally provides reliable,repeatable drug release characteristics.

In some embodiments, the drug units are relatively tall and slender,unlike conventional drug tablets that tend to be short and squat. Thedrug units may be tall enough to retain their orientation once loaded inthe drug reservoir, with reduced tipping or rolling. On the other hand,the drug units may be short enough to provide enough interstices orbreaks so that the device can flex or move along its length. Inparticular, each drug unit may have a length that exceeds its width,meaning an aspect ratio of height:width that is greater than 1:1.Suitable aspect ratios for the drug units may be in the range of about3:2 to about 5:2, although other aspect ratios are possible, includingaspect ratios that are less than 1:1, like conventional drug tablets. Anexample is shown in FIG. 1, which illustrates the drug unit 112 with alength that exceeds its diameter.

In embodiments in which the solid drug tablets are designed forinsertion or implantation in a lumen or cavity in the body, such as thebladder, via a drug delivery device, such as a device of the typedescribed above with reference to FIGS. 1-3, the drug tablets may be“mini-tablets” that are suitably sized and shaped for insertion througha natural lumen of the body, such as the urethra. For the purpose ofthis disclosure, the term “mini-tablet” generally indicates a solid drugtablet that is substantially cylindrical in shape, having end faces thatare relatively planar or flat and a side face that is substantiallycylindrical. An example mini-tablet is shown in FIG. 1. The mini-tablet112 has a diameter, extending along the end face, in the range of about1.0 to about 3.2 mm, such as between about 1.5 and about 3.1 mm. Themini-tablet has a length, extending along the side face, in the range ofabout 1.7 mm to about 4.8 mm, such as between about 2.0 mm and about 4.5mm. The friability of the tablet may be less than about 2%. Embodimentsof solid drug tablets and systems and methods of making the same arefurther described below with reference to U.S. patent applicationsincorporated by reference herein.

In a preferred embodiment, the drug tablets include lidocaine. A drugdelivery device having drug tablets that primarily comprise lidocainemay be wholly deployed in the bladder of a patient in need of treatmentfor interstitial cystitis, neurogenic bladder, or pain, among others.Other diseases or conditions may also be treated using this device. Inother embodiments, other drugs, alone or in combination with lidocaine,may be used to treat interstitial cystitis or other diseases andconditions involving the bladder.

Once the solid drug tablets are formed, the drug tablets may be loadedinto the drug delivery device. After the device is loaded, the devicepreferably is sterilized. The selected sterilization process does notundesirably alter the physical or chemical composition of the solid drugtablets or other components of the device. Examples of suitablesterilization processes include gamma irradiation or ethylene oxidesterilization, although other sterilization processes may be used. Forexample, gamma irradiation at a strength of about 8 KGy to about 40 KGy,such as about 25 KGy, can be employed.

The drug tablets can be formed using a stable and scalable manufacturingprocess and are suitable for the intended use. Particularly, the drugtablets are sized and shaped for loading into and efficiently storingthe tablets in a linear array in a drug delivery device that can bedeployed into the bladder or another cavity, lumen, or tissue site in apatient in a minimally invasive manner.

In addition, the drug tablets can be sterilized before or afterloading/assembly into a drug delivery device, and the drug tabletspossess a commercially reasonable shelf life. Once implanted, thecomposition of the drug tablets is appropriate for the intended route ofadministration, is stable in acidic conditions, and providespre-selected, reproducible drug release kinetics. For example, the drugtablets may be solubilized in the bladder to continuously release drugat a suitably stable rate drug over an extended period.

Although mini-tablets and other solid drug tablets are described aboveas having a high weight fraction of drug or API and a low weightfraction of excipients, the solid drug tablets may have any weightfraction of drug, especially in cases in which the tablet includes adrug that is extremely potent, a stabilizing agent, or an agent thatincreases the solubility of the drug, among others or combinationsthereof.

The Retention Frame Portion

The drug delivery device may include a retention frame portion. Theretention frame portion is associated with the drug reservoir portionand permits retaining the drug reservoir portion in the body, such as inthe bladder. The retention frame portion may include a retention framethat is deformable between a relatively expanded shape and a relativelylower-profile shape. For example, the retention frame may naturallyassume the relatively expanded shape, may be manipulated into therelatively lower-profile shape for insertion into the body, and mayspontaneously return to the relatively expanded shape upon insertioninto the body. The retention frame in the relatively expanded shape maybe shaped for retention in a body cavity, and the retention frame in therelatively lower-profile shape may be shaped for insertion into the bodythrough the working channel of a deployment instrument such as acatheter or cystoscope. To achieve such a result, the retention framemay have an elastic limit, modulus, and/or spring constant selected toimpede the device from assuming the relatively lower-profile shape onceimplanted. Such a configuration may limit or prevent accidentalexpulsion of the device from the body under expected forces. Forexample, the device may be retained in the bladder during urination orcontraction of the detrusor muscle.

In a preferred embodiment, the retention frame includes or consists ofan elastic wire. In one embodiment, the elastic wire may comprise abiocompatible shape-memory material or a biodegradable shape memorypolymer as described in U.S. Pat. No. 6,160,084 to Langer et al. Theelastic wire also may include a relatively low modulus elastomer, whichmay be relatively less likely to irritate or cause ulcer within thebladder or other implantation site and may be biodegradable so that thedevice need not be removed. Examples of low modulus elastomers includepolyurethane, silicone, styrenic thermoplastic elastomer, andpoly(glycerol-sebacate) (PGS). The elastic wire may be coated with abiocompatible polymer, such as a coating formed from one or more ofsilicone, polyurethane, styrenic thermoplastic elastomer, Silitek,Tecoflex, C-flex, and Percuflex.

For example, in the embodiment shown in FIGS. 1-2, the retention frame114 is an elastic wire formed from a superelastic alloy, such asnitinol, and surrounded by the wall 124 of the retention frame lumen110, which forms a protective sheath about the retention frame 114. Thewall 124 may be formed from a polymer material, such as silicone. Inother embodiments, the retention frame may be an elastic wire formedfrom a superelastic alloy, such as nitinol, that is covered in a polymercoating such as a silicone sheath and is attached to the drug reservoirportion.

In some embodiments, the retention frame lumen 110 may include theretention frame 114 and a filling material, such as a polymer filling.An example filling material is a silicone adhesive, such as MED3-4213 byNusil Technology LLC, although other filling materials may be used. Thefilling material may fill the void in the retention frame lumen 110about the retention frame 114. For example, the filling material may bepoured into the retention frame lumen 110 about the retention frame 114and may cure therein. The filling material may reduce the tendency ofthe drug reservoir lumen 108 to stretch along, or twist or rotate about,the retention frame 114, while maintaining the drug reservoir lumen 108in a selected orientation with reference to the retention frame 114. Thefilling material is not necessary, however, and may be omitted.

When the retention frame is in the relatively expanded shape, such asthe coiled shapes shown in FIG. 1, the device may occupy a space havingdimensions suited to impede expulsion from the bladder. When theretention frame is in the relatively lower-profile shape, such as theelongated shapes shown in FIG. 2, the device may occupy an area suitedfor insertion into the body, such as through the working channel of adeployment instrument. The properties of the elastic wire cause thedevice to function as a spring, deforming in response to a compressiveload but spontaneously returning to its initial shape once the load isremoved. The polymer coating may make the outer surface of the retentionframe relatively smooth and soft, reducing irritation of the bladder orother implantation site.

A retention frame that assumes a pretzel shape may be relativelyresistant to compressive forces. The pretzel shape essentially comprisestwo sub-circles, each having its own smaller arch and sharing a commonlarger arch. When the pretzel shape is first compressed, the larger archabsorbs the majority of the compressive force and begins deforming, butwith continued compression the smaller arches overlap, and subsequently,all three of the arches resist the compressive force. The resistance tocompression of the device as a whole increases once the two sub-circlesoverlap, impeding collapse and voiding of the device as the bladdercontracts during urination.

In embodiments in which the retention frame comprises a shape-memorymaterial, the material used to form the frame may “memorize” andspontaneously assume the relatively expanded shape upon the applicationof heat to the device, such as when exposed to body temperatures uponentering the bladder.

The retention frame may be in a form having a high enough springconstant to retain the device within a body cavity, such as the bladder.A high modulus material may be used, or a low modulus material.Especially when a low-modulus material is used, the retention frame mayhave a diameter and/or shape that provide a spring constant withoutwhich the frame would significantly deform under the forces ofurination. For example, the retention frame may include one or morewindings, coils, spirals, or combinations thereof, specifically designedto achieve a desirable spring constant, such as a spring constant in therange of about 3 N/m to about 60 N/m, or more particularly, in the rangeof about 3.6 N/m to about 3.8 N/m. Such a spring constant may beachieved by one or more of the following techniques: increasing thediameter of the elastic wire used to form the frame, increasing thecurvature of one or more windings of the elastic wire, and addingadditional windings to the elastic wire. The windings, coils, or spiralsof the frame may have a number of configurations. For example, the framemay be in a curl configuration comprising one or more loops, curls orsub-circles. The ends of the elastic wire may be adapted to avoid tissueirritation and scarring, such as by being soft, blunt, inwardlydirected, joined together, or a combination thereof.

Examples are shown in FIG. 5. The retention frame may have atwo-dimensional structure that is confined to a plane, athree-dimensional structure, such as a structure that occupies theinterior of a spheroid, or some combination thereof. In particular,Examples A through G illustrate frames comprising one or more loops,curls, or sub-circles, connected either linearly or radially, turning inthe same or in alternating directions, and overlapping or notoverlapping. Examples H through N illustrate frames comprising one ormore circles or ovals arranged in a two-dimensional or athree-dimensional configuration, the circles or ovals either closed oropened, having the same or different sizes, overlapping or notoverlapping, and joined together at one or more connecting points. Theretention frame portion also may be a three-dimensional structure thatis shaped to occupy or wind about a spheroid-shaped space, such as aspherical space, a space having a prorate spheroid shape, or a spacehaving an oblate spheroid shape. Examples O through R illustrateretention frame portions that are shaped to occupy or wind about aspherical space, with each retention frame portion shown above arepresentation of the frame in a sphere. The retention frame portion maygenerally take the shape of two intersecting circles lying in differentplanes as shown in Example O, two intersecting circles lying indifferent planes with inwardly curled ends as shown in Example P, threeintersecting circles lying in different planes as shown in Example Q, ora spherical spiral as shown in Example R. In each of these examples, theretention frame portion can be stretched to the linear shape fordeployment through a deployment instrument. The retention frame portionmay wind about or through the spherical space, or other spheroid-shapedspace, in a variety of other manners. One or both of the retention frameand retention housing may be omitted, in which case the retentionportion may be components of the drug portion itself, which may assumeor may be deformed into a retention shape, or the retention portion maybe an anchor associated with the drug portion. Examples of alternativeconfigurations are described in the U.S. patent applicationsincorporated by reference herein.

Other Device Features

The drug reservoir portion can include a coating or a sheath, which maybe substantially impermeable to water or relatively less permeable towater than the drug reservoir portion to reduce or alter the osmotic ordiffusive surface area of the device body. Thus, the release rate can beindependently controlled or targeted with reduced adjustment of desireddevice characteristics, such as size, shape, material, permeability,volume, drug payload, flexibility, and spring constant, among others. Toachieve the release rate, the coating or sheath may cover all or anyportion of the device body, and the coating or sheath may be relativelyuniform or may vary in thickness, size, shape, position, location,orientation, and materials, among others and combinations thereof.Further, multiple coatings or sheaths may be provided along differentportions of the device body, about the same drug reservoir or differentdrug reservoirs housing the same or different drug formulations. Incases in which the drug reservoir portion is formed from siliconetubing, for example, a coating may be formed from parylene, while asheath may be formed from a polymer such as polyurethane or curablesilicone, or another biocompatible coating or sheath material known inthe art. In some embodiments, the coating or sheath may be positioned onthe tube between the end and the orifice so that water permeatingthrough the tube adjacent to the end can drive through the portion ofthe tube covered by the sheath and out of the orifice, reducing oravoiding isolation or stagnation of the drug under the sheath. Coatingsand sheaths, and equations for selecting such designs, are described inU.S. Patent Publication No. 2009/0149833.

In one embodiment, the device includes at least one radio-opaque portionor structure to facilitate detection or viewing (e.g., by X-ray imagingor fluoroscopy) of the device by a medical practitioner as part of theimplantation or retrieval procedure. In one embodiment, the tube isconstructed of a material that includes a radio-opaque filler material,such as barium sulfate or another radio-opaque material known in theart. Some tubing may be made radio-opaque by blending radio-opaquefillers, such as barium sulfate or another suitable material, during theprocessing of the tubing. The radio-opaque material also may beassociated with the retention frame. For example, a platinum wire may bewound about ends of the elastic wire and covered in smootheningmaterial. Ultrasound imaging may be used. Fluoroscopy may be thepreferred method during deployment/retrieval of the non-erodible deviceby providing accurate real-time imaging of the position and orientationof the device to the practitioner performing the procedure.

In one embodiment, the body of the implantable drug delivery devicefurther includes at least one retrieval feature, such as a structurethat facilitates removal of the device from the body cavity, for examplefor removal of a non-resorbable device body following release of thedrug formulation.

One example of a retrieval feature is a string, formed of abiocompatible material. The string may be attached to a mid-portion oran end-portion of the drug delivery device. In some embodiments, thestring is sized to extend along the urethra from the bladder to theexterior of the body, in which case a proximal end of the string may bepositioned outside of the body once the device is positioned in thebladder. The string also may be shorter in size, so that once the deviceis positioned in the bladder, the proximal end of the string ispositioned in the urethra in a location that is reachable by aphysician. In either case, the device may be removed from the bladder byengaging the string to pull the device through the urethra. In suchembodiments, the diameter of the string may be sized to fit comfortablyin the urethra during the period of implantation. In other embodiments,the string is sized to be wholly implanted in the bladder with thedevice, in which case the string facilitates locating and grasping thedevice within the bladder using a removal instrument positioned in theurethra, such as a cystoscope or catheter.

In embodiments in which the string is attached to a mid-portion of thedrug delivery device, the device may fold upon itself as it enters theremoval instrument or the urethra. Folding at the mid-portion may befacilitated once the drug delivery device has released at least aportion of the drug or is empty. In embodiments in which the string isattached to an end-portion of the drug delivery device, the device maymove into the deployment shape as it enters the removal instrument orthe urethra. Thus, the deployment shape also may be considered aretrieval shape in such embodiments.

Embodiments of retrieval features are described in U.S. PatentPublication No. 2007/0202151 A1. In these and in other embodiments, thedevice may be retrieved using conventional endoscopic graspinginstruments, such as alligator forceps, three or four-pronged opticalgraspers. For example, if the device has an O-shaped or coiled portion,the removal of the device can be facilitated by those graspinginstruments.

Combination of the Components

The drug reservoir portion and the retention frame portion areassociated with each other to form the drug delivery device. A varietyof different associations are envisioned. For example, the drugreservoir portion and the retention frame portion may be at leastpartially aligned. In other words, the drug reservoir portion may extendalong a portion or the entire length of the retention frame portion,substantially parallel or coincident with the retention frame portion.An example of such an embodiment is shown in FIGS. 1-3. FIG. 6 alsoillustrates several alternative embodiments in cross-section. As shownin Examples F, G, H, and I, the retention frame wire may extend alongeither an exterior surface of the drug reservoir wall, along an interiorsurface of the drug reservoir wall, through the drug reservoir wall, orwithin a reinforced area inside or outside of the wall. As shown inExamples J, K, and L, the elastic wire may also be positioned within theinterior of the tube supported by a web, which may partition the tubeinto multiple compartments. The web may be perforated or otherwisenon-continuous so that the compartments are in communication with eachother, or the web may be relatively continuous such that thecompartments are segregated from each other to form different reservoirsthat may be suited for holding different drug formulations. The web maybe formed from the same material as the tube, or from a material havinga different permeability to water or urine, depending on the embodiment.As shown in Examples M, N, and O, the elastic wire may be associatedwith multiple tubes, extending along or between the tubes. The elasticwire may be embedded in a reinforcement area that joins togethermultiple discrete tubes. The tubes may hold the same or different drugformulations and also may be formed from the same or different materialsof construction, such as materials that differ in permeability to urineor other aqueous or bodily fluids.

In other embodiments, the drug reservoir portion may be attached to onlya portion of the retention frame. The drug reservoir portion may havefirst and second end portions that are attached to a portion of theretention frame. The end portions of the drug reservoir may terminate atthe retention frame, the end portions may overlap the retention frame,or a combination thereof. The drug reservoir portion may be orientedwith reference to the retention frame portion such that the drugreservoir portion lies within the perimeter of the retention frameportion, beyond the perimeter of the retention frame portion, or acombination thereof. Additionally, a number of drug reservoir portionsmay be associated with a single retention frame portion. Examples Athrough E of FIG. 6 illustrate such embodiments.

In other embodiments, the drug reservoir portion and the retention frameportion may be the same component in some embodiments. In such cases,the device may comprise a tube formed in a configuration having asufficient spring constant to retain the device in the body, asdescribed above. Also, the drug reservoir portion may be wrapped aroundthe retention frame portion, one or any number of times.

The embodiments described herein may be combined and varied to produceother drug delivery devices that fall within the scope of the presentdisclosure. For example, the drug reservoir portion may be attached toany portion of the retention frame portion in any manner. Multiple drugreservoir portions may be provided, a single drug reservoir portion maybe partitioned, or a combination thereof, which may facilitatedelivering multiple different drugs into the body, delivering differentforms of drugs into the body, delivering drugs at varying rates into thebody, or a combination thereof.

Furthermore, when the device is in the retention shape, the retentionframe portion may have any orientation with reference to the drugreservoir portion, laying either inside, outside, above, or below thedrug reservoir portion or moving with reference to the drug reservoirportion as the device moves through the implantation site. For example,the device 100 includes a retention frame portion that lies inside theperimeter of the drug reservoir portion. In other embodiments, thedevice includes a retention frame portion that lies below the drugreservoir portion (such that the retention frame portion would not bevisible in FIG. 1). A particular orientation between the two portionscan be maintained by filling the retention frame portion with a fillingmaterial, such as a silicone adhesive, after the retention frame isloaded. The filling material may cure or solidify to prevent movement ofone portion with reference to the other. Other means of maintaining theorientation of the retention frame portion with reference to the drugreservoir portion also can be used.

The aperture may be positioned inside the perimeter of the device,outside of the perimeter of the device, or an upper or lower plane ofthe device. For example, the device 100 includes an aperture 118 locatedon an outside perimeter of the device, but in other embodiments theaperture is located on an upper plane of the device. An aperturepositioned on the inside perimeter or on the upper or lower plane of thedevice advantageously may be less likely to become positioned directlyadjacent to a portion of the implantation site, such as the bladderwall, delivering a large quantity of drug to one particular location.The aperture also may be formed in a groove or indent defined betweenthe walls of the drug reservoir portion and the retention frameportions, so that the walls serve as bumpers that impede the aperturefrom becoming positioned directly adjacent to the implantation site. Forexample, the aperture 118 of the device 100 could instead be formed in agroove or indent between the walls 122 and 124.

For ease of manufacturing, the aperture may be formed through the wallof the drug reservoir portion on an opposite side from the retentionframe portion, as shown in FIG. 3. When the aperture is positionedopposite from the retention frame portion, it may be desirable to securethe retention frame portion below the device as described above, so thatthe aperture becomes positioned above the device, reducing the risk ofthe aperture becoming positioned on the outside perimeter of the device.However, other configurations are possible.

It should be noted that the device 400 shown in FIG. 4 has a slightlydifferent shape and configuration than the device 100 shown in FIG. 1.For example, the ends of the device 400 are relatively straighter thanthe ends of device 100. The straighter ends may result because theretention frame of the device 400 has relatively straight end portions,while the retention frame of the device 100 has relatively curved endportions. A retention frame with relatively straight end portions may beless likely to puncture the walls of the device body during drug loadingand thereafter, reducing the risk of device failure after implantation.However, either retention frame shape can be used.

In the embodiment shown in FIG. 1, for example, the drug delivery device100 is suited for delivering a drug into the bladder. The drug reservoirlumen 108 may have an inner diameter of about 1.3 to about 3.3 mm, suchas about 1.5 to about 3.1 mm, an outer diameter of about 1.7 to about3.7 mm, such as about 1.9 to about 3.4 mm, and a length of about 12 to21 cm, such as about 14 to 16 cm. The drug reservoir lumen 108 may holdabout 10 to 100 cylindrical drug tablets, such mini-tablets. Themini-tablets may each having a diameter of about 1.0 to about 3.3 mm,such as about 1.5 to about 3.1 mm, and a length of about 1.5 to about4.7 mm, such as about 2.0 to about 4.5 mm. Such mini-tablets may have alidocaine payload of about 3.0 to about 40.0 mg. One particular exampleof a mini-tablet may have a diameter of about 1.52 mm, a length of about2.0 to 2.2 mm, and a mass of about 4.0 to 4.5 mg lidocaine. Anotherparticular example of a mini-tablet may have a diameter of about 2.16mm, a length of about 2.9 to 3.2 mm, and a mass of about 11.7 to 13.1 mglidocaine. Yet another particular example of a mini-tablet may have adiameter of about 2.64 mm, a length of about 3.5 to 3.9 mm, and a massof about 21.3 to 23.7 mg lidocaine. Still another particular example ofa mini-tablet may have a diameter of about 3.05 mm, a length of about4.1 to 4.5 mm, and a mass of about 32.7 to 36.9 mg lidocaine. However,other diameters, lengths, and masses can be used.

Within these ranges, the device may be designed to deliver between about150 mg and 1000 mg of lidocaine to the bladder, such as about 200 mg,about 400 mg, about 600 mg, or about 800 mg of lidocaine. For example, asmaller payload may be delivered from a smaller device or from a deviceloaded with fewer tablets, the remainder of the space in the devicebeing loaded with a spacer or filling material.

The foregoing specific configurations are merely possibilities of thetype of devices that may be created by a person skilled in the art uponreading the present disclosure. For example, in some embodiments thedrug reservoir portion may be omitted completely, and the retentionframe portion may be associated with another component for retention inthe body, such as the bladder. Examples of other components includediagnostic equipment, test materials, and small electronic devices, suchas cameras and sensors, among others.

II. Method of Making the Device

An embodiment of a method of making an implantable drug delivery devicemay include forming a drug delivery device, forming a number of drugtablets, and loading the drug tablets into the drug delivery device.

In embodiments, forming the drug delivery device may include one or moreof the following sub-steps: forming a device body, forming a retentionframe, associating the device body with the retention frame, and formingone or more apertures in the device body.

Forming the device body may include forming a flexible body having wallsthat define a drug reservoir lumen and a retention frame lumen. Forexample, the device body may be formed by extruding or molding apolymer, such as silicone. In particular, forming the device body mayinclude integrally forming two tubes or walls that are substantiallyaligned and adjoined along a longitudinal edge. Alternatively, the twolumens may be separately formed and attached to each other, such as withan adhesive. Other methods of forming the device body also may beemployed.

Forming a retention frame may include forming an elastic wire from, forexample, a superelastic alloy or shape-memory material and “programming”the elastic wire to naturally assume a relatively expanded shape. Heattreatment may be used to program the elastic wire to assume the expandedshape. For example, the retention frame may be formed by forming theelastic wire into a pretzel shape and heat treating the elastic wire ata temperature over 500° C. for a period over five minutes. Inembodiments in which the retention frame comprises a low moduluselastomer, the step of forming the vesical retention frame maycomprising forming one or more windings, coils, loops or spirals in theframe so that the frame functions as a spring. For example, theretention frame may be formed by extrusion, liquid injection molding,transfer molding, or insert molding, among others.

Associating the device body with the retention frame may compriseinserting the retention frame into the retention frame lumen of thedevice body. In some embodiments, a distal end of the retention frame isblunted or is covered in a smooth ball of increased cross section duringinsertion of the retention frame into the lumen. The ball may facilitatedriving the retention frame through the retention frame lumen withoutpuncturing the wall of the device body. Also in some embodiments, thedevice body may be slightly compressed between two surfaces during theinsertion of the retention frame. Compressing the device body elongatesthe opening into the retention frame lumen, facilitating loading.

In some embodiments, associating the device body with the retentionframe further includes filling the retention frame lumen with a fillingmaterial after the retention frame is loaded. The filling materialoccupies the remainder of the lumen not occupied by the retention frame,reducing the ability of the device body to stretch along, or twist orrotate about, the retention frame. For example, silicone or anotherpolymer may be injected or poured into the retention frame lumen and maycure therein. In other embodiments, associating the device body with theretention frame portion may comprise integrally forming the two portionstogether, such as by overmolding the device body about the retentionframe.

Forming one or more apertures in the device body may include laserdrilling or mechanically punching one or more holes in the device body.The apertures also may be formed simultaneously with the device body,such as by molding with an indenter as described in U.S. Pat. No.6,808,522 to Richards et al.

The drug tablets made by a direct compression tableting process, amolding process, or other processes known in the pharmaceutical arts.Suitable drug tablet forming methods are described in U.S. patentapplications incorporated by reference herein.

The drug tablets may be loaded into the drug delivery device bypositioning one or more drug tablets upstream of the drug deliverydevice adjacent to its entry and driving the drug tablets into the drugdelivery device with a flow of pressurized gas. Suitable drug tabletloading methods and systems are described in U.S. patent applicationsincorporated by reference herein. Other drug tablet loading methods canbe used.

Some steps or sub-steps of the method of making an implantable drugdelivery device may be performed in other orders or simultaneously. Forexample, the retention frame may be associated with the device bodyeither before or after the drug units are loaded into the device body.Similarly, the apertures may be formed in the device body either beforeor after the drug tablets are loaded.

In embodiments, the method of making an implantable drug delivery devicemay further include partitioning the drug reservoir lumen into multiplediscrete drug reservoirs, such as by positioning one or more partitionstructures within the drug reservoir lumen in an alternating fashionwith the loading of the drug tablets. In embodiments, the method mayfurther include sealing the drug tablets in the device body. The methodmay also include associating one or more release controlling structureswith the drug reservoir lumen, such as a sheath or coating placed overat least a portion of the surface of the device body to control the rateof release of the drug or a degradable membrane positioned over or inone or more of the apertures to control the initial time of release ofthe drug therethrough.

III. Use and Applications of the Device

The device may be implanted in a body cavity or lumen, and subsequentlymay release one or more drugs for the treatment of one or moreconditions, locally to one or more tissues at the deployment site and/orregionally to other tissues distal from the deployment site. The releasemay be controlled over an extended period. Thereafter, the device may beremoved, resorbed, excreted, or some combination thereof.

In one example, the device is implanted by passing the drug deliverydevice through a deployment instrument and releasing the device from thedeployment instrument into the body. In cases in which the device isdeployed into a body cavity such as the bladder, the device assumes aretention shape, such as an expanded or higher profile shape, once thedevice emerges from the deployment instrument into the cavity. Anexample is illustrated in FIG. 7, which shows the device 700 assuming aretention shape as the device exits a deployment instrument 702. Thedeployment instrument 702 may be any suitable lumen device, such as acatheter, urethral catheter, or cystoscope. These terms are usedinterchangeably herein, unless otherwise expressly indicated. Thedeployment instrument 702 may be a commercially available device or adevice specially adapted for the present drug delivery devices.

Once implanted, the device may release the drug. The device may provideextended, continuous, intermittent, or periodic release of a desiredquantity of drug over a desired, predetermined time period. Inembodiments, the device can deliver the desired dose of drug over anextended period, such as 12 hours, 24 hours, 5 days, 7 days, 10 days, 14days, or 20, 25, 30, 45, 60, or 90 days, or more. The rate of deliveryand dosage of the drug can be selected depending upon the drug beingdelivered and the disease or condition being treated.

In embodiments in which the device comprises a drug in a solid form,elution of drug from the device occurs following dissolution of the drugwithin the device. Bodily fluid enters the device, contacts the drug andsolubilizes the drug, and thereafter the dissolved drug diffuses fromthe device or flows from the device under osmotic pressure or viadiffusion. For example, the drug may be solubilized upon contact withurine in cases in which the device is implanted in the bladder.

Subsequently, the device may be retrieved from the body, such as incases in which the device is non-resorbable or otherwise needs to beremoved. Retrieval devices for this purpose are known in the art or canbe specially produced. The device also may be completely or partiallybioresorbable, such that retrieval is unnecessary, as either the entiredevice is resorbed or the device sufficiently degrades for expulsionfrom the bladder during urination. The device may not be retrieved orresorbed until some of the drug, or preferably most or all of the drug,has been released. If needed, a new drug-loaded device may subsequentlybe implanted, during the same procedure as the retrieval or at a latertime.

FIG. 8 illustrates the implantation of a device 800 into the bladder,wherein the adult male anatomy is shown by way of example. A deploymentinstrument 802 may be inserted through the urethra to the bladder, andthe device 800 may be passed through the deployment instrument 802,driven by a stylet or flow of lubricant or other fluid, for example,until the device 800 exits into the bladder. Thus, the device isimplanted into the bladder of a male or female human patient in need oftreatment, either adult or child.

The device may be deployed into the bladder of a patient in anindependent procedure or in conjunction with another urological or otherprocedure or surgery, either before, during, or after the otherprocedure. The device may release one or more drugs that are deliveredto local and/or regional tissues for therapy or prophylaxis, eitherperi-operatively, post-operatively, or both.

In one embodiment, the implantable device, with a self-contained drugpayload, is deployed wholly within the bladder to provide local,sustained delivery of at least one drug locally to the bladder in aneffective amount. Following in vivo deployment of the device, at least aportion of the payload of drug is released from the device substantiallycontinually over an extended period, to the urothelium and possibly tonearby tissues, in an amount effective to provide treatment or toimprove bladder function in the patient. In a preferred embodiment, thedevice resides in the bladder releasing the drug over a predeterminedperiod, such as two weeks, three weeks, four weeks, a month, or more.

In such cases, the device may be used to treat interstitial cystitis,radiation cystitis, pelvic pain, overactive bladder syndrome, bladdercancer, neurogenic bladder, neuropathic or non-neuropathicbladder-sphincter dysfunction, infection, post-surgical pain or otherdiseases, disorders, and conditions treated with drugs delivered to thebladder. The device may deliver drugs that improve bladder function,such as bladder capacity, compliance, and/or frequency of uninhibitedcontractions, that reduce pain and discomfort in the bladder or othernearby areas, or that have other effects, or combinations thereof. Thebladder-deployed device also may deliver a therapeutically effectiveamount of one or more drugs to other genitourinary sites within thebody, such as other locations within urological or reproductive systemsof the body, including one or both of the kidneys, the urethra, one orboth of the ureters, the penis, the testes, one or both of the seminalvesicles, one or both of the vas deferens, one or both of theejaculatory ducts, the prostate, the vagina, the uterus, one or both ofthe ovaries, or one or both of the fallopian tubes, among others orcombinations thereof. For example, the intravesical drug delivery devicemay be used in the treatment of kidney stones or fibrosis, erectiledysfunction, among other diseases, disorders, and conditions.

In some embodiments, the intravesical drug delivery device is deployedinto the bladder of a patient for regional drug delivery to one or morenearby genitourinary sites. The device may release drug locally to thebladder and regionally to other sites near the bladder. Such deliverymay provide an alternative to systemic administration, which may entailundesirable side effects or result in insufficient bioavailability ofthe drug.

In one embodiment, the intravesical drug delivery device is implantedinto a bladder to locally deliver a local anesthetic agent formanagement of pain arising from any source, such as a disease ordisorder in genitourinary tissues, or pain stemming from any bladderprocedure, such as surgery, catheterization, ablation, medical deviceimplantation, or stone or foreign object removal, among others.

In some cases, the device can release a local anesthetic agent into thebladder for regional delivery to nearby sites, as described in Example 9below. The local anesthetic agent can facilitate the management ofnearby pain arising from any source. For example, the device may releasea local anesthetic agent into the bladder for the purpose of treatingpost-operative pain in sites apart from the bladder. In one example, thedrug delivery device implanted in the bladder may release a drug totreat post-operative pain associated with the passage of a medicaldevice into or through a ureter. The device also may achieve regionaldelivery of drugs other than local anesthetic agents, and the devicethrough regional delivery may treat conditions other than post-operativepain.

In one particular embodiment, a device having a payload of lidocaine maybe delivered to the bladder, and lidocaine may be continuously releasedfrom the device over an extended period. In one embodiment, localdelivery of lidocaine to the urothelium of the bladder is provided fromthe presently disclosed devices which have been deployed into thebladder in a manner which achieves a sustained level of lidocaine abovethe concentration that could be obtained for an extended period viainstillation, yet without the high initial peak observed withinstillation and without significant systemic concentrations. Thereby, asmall payload may be implanted, reducing the risk of systemic effects inthe event of device failure. Implanting lidocaine in solid form permitsfurther reducing the size of the device to reduce bladder irritation andpatient discomfort. The lidocaine may be delivered without regard to thepH of the urine. In one embodiment, the device may have two payloads oflidocaine that are released at different times. The first payload may beadapted for relatively quick release, while the second payload may beadapted for more continuous release. For example, the first payload maybe in liquid form or may be housed in a relatively fast-acting osmoticpump, such as a silicone tube having a relatively thinner wall, whilethe second payload may be solid form or may be housed in an osmotic pumpthat experiences an initial delay or induction time before releasing,such as a silicone tube having a relatively thicker wall. Thus, themethod may continuously release lidocaine into the bladder during aninitial, acute phase and during a maintenance phase. Such a method maycompensate for an initial induction time of the device.

Methods of Use of the Tolerable and Unnoticeable Device

Examples 4, 5, 6, and 7 describe in vivo studies that show that the drugdelivery devices described herein upon being deployed in the bladder ofa human or dog may be surprisingly well tolerated, and in the case ofthe humans, more unexpectedly, may be essentially unnoticeable in thebladder. That is, a device described herein cannot be felt by thepatient. Based on this tolerability discovery, certain new methods oftreatment of human patients may be provided.

This attribute of the present devices enables the physicians to selectdrug therapies for indications where just being tolerable does notoutweigh the benefit gained by the delivery of drug. The highlytolerable (unnoticeable) device described herein can extend local drugtherapy to the bladder beyond those patients with high unmet medicalneeds, to include those who may want to consider therapeuticalternatives to current strategies. For example, patients withrefractory over active bladder disease (failing one or moreanticholinergics agents due to lack of efficacy or side effects) wouldlikely tolerate a system for local delivery of drug that might have lessthan favorable tolerability profile. A device that cannot be noticed inthe bladder could, however, extend treatment to patients with lesssevere disease and be directly competitive with first-line oralanticholinergics use. Another example is for the treatment of patientswith chronic urinary tract infections. Standard of care is daily oralantibiotic use for months at a time to suppress bladder infections. Thehighly tolerable device described here may supplant chronic oral therapyand provide a superior therapeutic option due to less of a concern withpatient compliance (forgetting a dose) which can lead to bacterialresistance. Additional examples where bladder tolerability is a primaryconcern include interstitial cystitis, radiation cystitis, painfulbladder syndrome, prostatitis, urethritis, urinary incontinence, urgeincontinence, neurogenic incontinence, trigonitis, spastic neurogenicbladder, flaccid neurogenic bladder, bladder infection, prostateinfection, urethra infection, perioperative pain associated withurological procedure or surgery, and postoperative pain associated withurological procedure or surgery.

In one embodiment, the method includes selecting a patient in need oftreatment in the bladder where tolerability of the treatment is aprimary concern; deploying a drug delivery device into the patient'sbladder; and releasing a drug from the deployed drug delivery device,wherein the deployed drug delivery device is unusually well tolerated bythe patient. As used herein, the phrase “patient in need of treatment inthe bladder where tolerability of the treatment is a primary concern”means that at least one alternative drug therapy, e.g., an oral drugtherapy, is available for administration to the patient for the purposeof meeting the patient's need for treatment, which alternative therapydoes not include deployment of a drug delivery device into the patient'sbladder. Selection of such a patient is made before it is known whetherthe alternative oral drug therapy would be effective in the particularpatient. Tolerability is not a primary concern where the patient is inneed of treatment of a life-threatening condition or where no oral drugtherapy is available and effective for the patient. Tolerability isprimary concern where the patient is in need of treatment of a chroniccondition where alternative first line drug treatments exist and areavailable.

In one embodiment, a method of treatment of a human patient is providedwhich includes (i) selecting a patient in need of treatment in thebladder where tolerability of the treatment is a primary concern; (ii)deploying a drug delivery device into the patient's bladder through thepatient's urethra; and (iii) releasing a drug into the bladder from thedeployed drug delivery device over a treatment period, which may lastseveral days or weeks. In a preferred embodiment, the patient cannotfeel the deployed device within his or her bladder during at least amajority of the treatment period.

The present invention may be further understood with reference to thefollowing non-limiting examples.

Example 1: A Drug Delivery Device

A drug delivery device, schematically illustrated in FIG. 9, was createdin accordance with the description provided above. The device included asilicone body having two lumens. A larger lumen was loaded with solidtablets of lidocaine hydrochloride for a total drug payload of about 275mg. A smaller lumen was loaded with a nitinol wireform having a diameterof about 0.23 mm. The nitinol wireform generally retained the device inthe illustrated rest shape. In the rest shape, the device generallyrested in a plane defined by a minor or short axis, which was an axis ofsymmetry for the device, and a major or long axis, which was generallyperpendicular to the minor or short axis. A width or maximum dimensionof the device along the major axis was approximately 35 mm, and a heightor maximum dimension of the device along the minor axis wasapproximately 30 mm. A thickness of the device, in a directionperpendicular to the rest plane, was approximately 2.6 mm. Whenuncoiled, the device had a length of about 17 cm. The density of thedevice when loaded with tablets and dry was approximately 1.15 g/cm³.

Example 2: A Placebo Device

A placebo device also was fabricated. The placebo device was identicalto the device described above with reference to in Example 1 except thatthe device did not contain any drug tablets in its larger lumen.Therefore, the placebo device had the same parameters as the device ofExample 1, except that the placebo device had a density of about 0.62g/cm³.

Example 3: Another Drug Delivery Device

Another drug delivery device, schematically illustrated in FIG. 10, wascreated in accordance with the description provided above. The deviceincluded a silicone body having two lumens. A larger lumen was loadedwith solid tablets of lidocaine hydrochloride for a total drug payloadof about 895 mg. A smaller lumen was loaded with a nitinol wireformhaving a diameter of about 0.28 mm. The nitinol wireform generallyretained the device in the illustrated rest shape. In the rest shape,the device generally rested in a plane defined by a minor or short axis,which was an axis of symmetry for the device, and a major or long axis,which was generally perpendicular to the minor or short axis. A width ormaximum dimension of the device along the major axis was approximately45 mm, and a height or maximum dimension of the device along the minoraxis was approximately 35 mm. A thickness of the device, in a directionperpendicular to the rest plane, was approximately 3.75 mm. Whenuncoiled, the device had a length of about 17 cm. The density of thedevice when loaded with tablets and dry was approximately 1.20 g/cm³.

Example 4: First Tolerability Study

A Phase 1 study (TAR-100-101) was performed to assess subject toleranceof a drug delivery device in accordance with the present disclosure. Tenhealthy, adult, female human volunteer subjects participated in thestudy. The test devices were substantially similar to the placebo devicedescribed above with reference to Example 2. Seven subjects received atest device. The devices were inserted into and retrieved from thebladder via cystoscopy. The devices were inserted for fourteen days andthereafter were removed. Three subjects were subjected to a shamprocedure of cystoscopy only, during which no device was implanted inthe subject or removed.

Subject-reported symptoms were captured via a Subject TolerabilityAssessment (STA) visual analogue scale (VAS). The STA VAS consisted of a100 mm horizontal line with the word “Typical” at the left end and theword “Not Typical” at the right end. Subjects were instructed tocomplete the STA VAS by marking the spot on the line that describedtheir urinary voiding behavior within the last 24 hours and by markingthe spot on the line that described the sensation in their bladderwithin the last 24 hours. Additionally, subjects were given the optionto record any comments regarding their answers to the above questions.The STA was collected starting pre-insertion on Study Day 1 as abaseline and on all subsequent Study Days.

With reference to sensation in the bladder, the experiences of thosesubjects who received the test device were largely similar to theexperiences of those subjects who underwent the sham procedure. Withreference to urinary voiding behavior, the experiences of those subjectswho underwent who received the test device also were largely similar tothe experiences of those subjects who underwent the sham procedure. NoSerious Adverse Events were observed in this study. The study showedthat the test device was well tolerated.

Example 5: Second Tolerability Study

An animal study was conducted in dog using test devices substantially inaccordance with the device described above with reference to Example 1.Four large mixed breed hounds were employed in the study. A test devicewas implanted in each dog for 14 days. The test devices were welltolerated over the 14-day period without any significant clinicalobservations, such as change in weight, eating habits, or voidingbehavior. The study showed that the test device was well tolerated indog.

Example 6: Third Tolerability Study

Another animal study was conducted in dog using test devicessubstantially in accordance with the device described above withreference to Example 1. Nine female, mixed breed hounds were employed inthe study. A test device was placed in the bladder of each hound bycystoscopy. On day 14 after placement, the test device was removed and asecond test device of the same type was placed for another 14 days. Alltest devices were retained over the 14-day periods. All test devicesplaced in the first treatment period were identified in the bladder andremoved by cystoscopy after 14 days. All test devices placed in thesecond treatment period were identified in the bladder and removed bycystoscopy or necropsy after 14 days. No test devices were voidedprematurely. The test devices were well tolerated in female mixed breedhound dogs for 14 days. There were no test-device-related changes inclinical observations, body weights, food consumption, ophthalmologicalexams, electrocardiograms, and hematology, coagulation, and clinicalchemistry parameters. There was no evidence of local or systemictoxicity.

Example 7: Fourth Tolerability study

Another animal study was conducted in dog using test devicessubstantially in accordance with the device described above withreference to Example 3. Seven female, mixed breed hounds were employedin the study. A test device was placed in the bladder of some of thehounds via cystoscopy, while other hounds were subjected to a shamcystoscopy procedure that did not place a device in the bladder. On day14 after placement, the test device was removed and a second test deviceof the same type was placed for another 14 days, or a second shamprocedure was performed for the sham group. All test devices wereretained in female mixed breed hound dogs for 14 days. All test devicesplaced in the first treatment period were identified in the bladder andremoved by cystoscopy after 14 days. All test devices placed in thesecond treatment period were identified in the bladder and removed bycystoscopy or necropsy after 14 days. No test devices were voidedprematurely. The test devices were well tolerated in female mixed breedhound dogs for 14 days. There were no test device related changes inclinical observations, body weights, food consumption, ophthalmologicalexams, electrocardiograms, and hematology, coagulation, and clinicalchemistry parameters. There was no evidence of local or systemictoxicity.

Example 8: Resistance to Compression for Various Devices

Compression tests were performed on various devices to analyze thecompression behavior of the devices when exposed to compressive forces.Five different devices were subjected to the compression tests, and theresults of the tests are summarized in FIGS. 11 and 12. The testeddevices included a nitinol wire having a diameter of about 0.23 mm(shown in FIGS. 11 and 12 as the wire form of 0.009 inch thickness), anitinol wire having a diameter of about 0.28 mm thickness (shown inFIGS. 11 and 12 as the wire form of 0.011 inch thickness), a drug-loadeddevice that was substantially similar to the device described above inExample 1 (shown in FIGS. 11 and 12 as Device A), a placebo device thatwas substantially similar to the device described above in Example 2(shown in FIGS. 11 and 12 as the Placebo device for Device A), and adrug-loaded device that was substantially similar to the devicedescribed above in Example 3 (shown in FIGS. 11 and 12 as Device B).Both the placebo device and the loaded devices were gamma-irradiatedwith the dose of 25 kGy.

The devices were subjected to compression tests. Data was collected forone compression cycle. FIG. 11 illustrates compression along the longaxis, meaning compression that tends to change the shape of the devicealong its longer axis as a compressive force is applied to the devicealong its longer axis, while FIG. 12 illustrates compression along theshort axis, meaning compression that tends to change the shape of thedevice along its shorter axis as a compressive force is applied to thedevice along its shorter axis.

For the tests, the compression rate was set to 30 mm/min, and thecompressive load was recorded while the gap between two compressionplatens varied. The devices were compressed until the gap between thetwo compression platens was 15 mm. The results of the tests are plottedin FIGS. 11 and 12. For each device on each graph, the upper curve wasobtained during compression and the lower curve was obtained duringrelaxation

The force exerted by the loaded device of Example 1 during compressionto a gap distance of 30 mm was less than 0.01 N in both the long andshort axis. The force exerted by the placebo device of Example 2 duringcompression was similarly less than 0.01 N in both the long and shortaxis, at the same gap distance. Finally, the force exerted by the loadeddevice of Example 3 during compression to a gap distance of 30 mm was0.1 N in both the long and short axis.

Example 9: Regional Drug Delivery

A study was conducted in rabbit to investigate the biodistribution oflidocaine delivered from a drug delivery device implanted in thebladder. Four rabbits were used in the experiment. Each rabbit had atest device implanted in its bladder. The test devices had the generalshape and configuration shown in FIG. 6. Two of the rabbits received atest device housing 2 mg of lidocaine and were sacrificed after threedays, while the other two rabbits received a test device housing 4 mg oflidocaine and were sacrificed after six days.

The test device housing 2 mg of lidocaine included a nitinol wire formand a drug-loaded silicone tube. The wire form had a thickness of 0.2286mm and was covered with silicone tubing having an inner diameter of0.508 mm and an outer diameter of about 0.9398 mm. The drug-loadedsilicone tube had an inner diameter of about 0.3048 mm and an outerdiameter of about 0.635 mm. The tube was loaded with about 2 mg oflidocaine and was sealed at both ends. A hole having a diameter of about50 μm was formed about a middle of the tube, and the tube was attachedto the nitinol wire form, spanning its major width. Overall, the devicewas about 30 mm wide along its major axis, about 25 mm wide about itsminor axis, and about 1 mm thick.

The test device housing 4 mg of lidocaine was substantially the same inconfiguration as the test device housing 2 mg of lidocaine, except thatthe silicone tube had an inner diameter of about 0.508 mm and an outerdiameter of 0.9398 mm, and the tube was loaded with about 4 mg oflidocaine.

Tissue samples were taken from each of the rabbits, particular from thebladder, the ureters, the kidney, the heart, the spinal cord, and thepenile urethra of each rabbit. The ureter samples were taken from thedistal portion of each ureter. The kidney samples were taken from thecortex and medulla of one lobe. The heart samples were taken from themyocardium at the apex. The spinal cord samples were taken vialaminectomy from L5 to L7. The samples were subjected to enzyme-linkedimmunosorbent assay (ELISA) to detect lidocaine and its metabolites.

FIG. 13 is a biodistribution graph shows the lidocaine/tissueconcentration for each of the rabbits at each of the sampled locations.For each sampled location, FIG. 13 illustrates the concentrationdetected in the first three-day rabbit on the far left, the secondthree-day rabbit on the middle left, the first six-day rabbit on themiddle right, and the second six-day rabbit on the far right. As shown,the devices implanted in the bladder delivered higher concentrations oflidocaine to the bladder tissue and nearby genitourinary sites, such asthe kidneys, ureters, and penile urethra; whereas lower concentrationsof lidocaine were delivered to further sites such as the heart and thespinal cord. For the two rabbits that were euthanized after six days,the cerebrospinal fluid also was sampled just prior to euthanasia byspinal cord puncture at L7. Lidocaine was not detected in thecerebrospinal fluid of either rabbit.

Example 10: Resistance to Hydrodynamic Forces during Urination

A voiding experiment was conducted to empirically determine whetherdevices of the shape described above with reference to FIG. 1 couldresist hydrodynamic forces during urination. Any portion of the devicethat is located right above the internal urethral orifice duringurination will undergo hydrodynamic force. It was thought that eachdevice would resist the hydrodynamic forces associated with urination ifits associated wire had a sufficient stiffness.

Two devices were tested. One was substantially similar to the devicedescribed above with reference to Example 1 and the other wassubstantially similar to the device described above with reference toExample 2. The first device was calculated to have a bending springconstant of about 890 N/m, and the second device was calculated to havea bending spring constant of about 2000 N/m. The term bending springconstant generally connotes the spring constant related to bendingperpendicular to the wire axis. Using linear analysis, a correlationbetween the force and displacement was obtained.

The experiment was conducted in a vertical PVC tube with an open latexballoon at the bottom end, secured in place by a cap with a drilledhole. Voiding was simulated by filling the PVC tube with soapy water toa pre-determined height then allowing the water to flow freely throughthe latex balloon neck. The neck was confined to a diameter of about 6mm, controlled by the drilled hole in the cap, as the diameter of theinternal urethral orifice in women is about 6 mm. It was found that bothdevices that were modeled and tested indeed resisted the hydrodynamicforces during the voiding experiment.

Another observation was that the devices would not experience the mostsevere hydrodynamic forces during voiding if the devices were floatingat the beginning of the process, when the most severe hydrodynamicforces occur. The floating device approached the opening towards the endof voiding, when the fluid velocities and flow rates of water exitingthe orifice were lower. It was noted that a device could avoid voidingpotential voiding simply by not being located near the opening whenurination began, such as by having a density slightly lower. Such adevice would still need a minimum spring constant to resist the lowhydrodynamic forces at the end of urination, but the requirements couldbe significantly reduced.

It was also observed the device could be voided from the system if oneof its extremities or ends was located directly above the opening asvoiding occurred. This risk may be reduced by designing the device tohave no ends or so that its extremities does not approach the urethralopening when the device is either at rest or exposed to drag due to theby hydrodynamic forces.

Thus, a device that may be retained in a bladder during urination ifportions of the device that could be located near the urethral openingduring urination are able to resist maximum hydrodynamic forces duringurination; if the device has no extremities, or if the extremities arepositioned such that they cannot be located adjacent to the urethralopening; or if the device that is less dense than urine and thereby doesnot experience the maximum hydrodynamic forces during urination. Thedevice also may need to have a resistance to bending.

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

We claim:
 1. An intravesical drug delivery device, comprising: anelongated elastic body comprising a drug reservoir lumen definedtherein; and a drug formulation disposed within the drug reservoirlumen, the drug formulation comprising a drug which comprises a kinaseinhibitor, wherein the elongated elastic body has a coiled retentionshape having (i) dimensions that provide intravesical mobility andprevent voiding of the device through the urethra, and (ii) a maximumdimension in any direction of 6 cm or less when in an uncompressedstate, and wherein the device exerts a maximum acting force less than 1N when the device is compressed from the retention shape to a shapehaving a maximum dimension in any direction of 3 cm or less.
 2. Thedevice of claim 1, wherein the elongated elastic body comprises asilicone tube which comprises one or more apertures extending through asidewall of the silicone tube, and wherein the device is configured toprovide release of the drug through the one or more apertures, driven atleast in part by an osmotic pressure in the drug reservoir lumen.
 3. Thedevice of claim 2, wherein the one or more apertures have a diameterbetween 25 μm and 300 μm.
 4. The device of claim 2, wherein the one ormore apertures has a diameter between 100 μm and 200 μm.
 5. The deviceof claim 1, wherein the elongated elastic body comprises a tube whichcomprises polyurethane.
 6. The device of claim 1, wherein the elongatedelastic body has no apertures or passing pores, and the device isconfigured to release the drug by diffusion through a wall of theelastic body.
 7. The device of claim 1, wherein the drug formulationdisposed within the drug reservoir lumen comprises between 10 and 100mini-tablets.
 8. The device of claim 1, wherein the elongated elasticbody comprises two integrally formed tubes, which define the drugreservoir lumen and a retention frame lumen.
 9. The device of claim 8,further comprising a nitinol wireform disposed within the retentionframe lumen.
 10. The device of claim 1, wherein the device in theretention shape and uncompressed has a maximum dimension in anydirection that is less than 10 cm.
 11. The device of claim 1, whereinthe device in the retention shape and uncompressed has a maximumdimension in any direction that is less than 5 cm.
 12. The device ofclaim 1, wherein the device exerts a maximum acting force less than 1 Nwhen the device is compressed from the retention shape to a shape with amaximum dimension in any direction of 1.5 cm.
 13. A drug delivery devicefor deployment within the bladder of a human patient, the devicecomprising: an elongated elastic body which comprises two integrallyformed tubes, one of which defines a drug reservoir lumen and the otherwhich defines a retention frame lumen; a nitinol wireform disposed inthe retention frame lumen; and a drug formulation, comprising a drug,disposed within the drug reservoir lumen, wherein the drug formulationis in the form of a plurality of mini-tablets, wherein the elongatedelastic body has a coiled retention shape having (i) dimensions thatprovide intravesical mobility and prevent voiding of the device throughthe urethra, and (ii) a maximum dimension in any direction of 6 cm orless when in an uncompressed state and wherein the device exerts amaximum acting force less than 1 N when the device is compressed fromthe retention shape to a shape having a maximum dimension in anydirection of 3 cm or less.
 14. The device of claim 13, wherein the drugcomprises a kinase inhibitor.
 15. The device of claim 14, wherein theelastic body exerts a maximum acting force less than 1 N when compressedto a shape with a maximum dimension in any direction of 1.5 cm or less.16. The device of claim 14, wherein the tube defining the drug reservoirlumen comprises one or more apertures extending through a sidewall ofsaid tube, wherein the device is configured to provide release of thedrug through the one or more apertures, driven at least in part by anosmotic pressure in the drug reservoir lumen.
 17. The device of claim16, wherein the one or more apertures consists of an aperture having adiameter between 25 μm and 300 μm.
 18. The device of claim 16, whereinthe one or more apertures have a diameter between 100 μm and 200 μm. 19.The device of claim 16, wherein the one or more apertures are in asidewall position opposite from the tube defining the retention framelumen.
 20. The device of claim 14, wherein the drug is a low solubilitydrug, the elongated elastic body has no apertures or passing pores, andthe device is configured to release the drug by diffusion through a wallof the tube defining the drug reservoir lumen.
 21. A drug deliverydevice, comprising: an elongated elastic body comprising a first end, anopposed second end, a tubular intermediate portion disposed between thefirst and second ends, and a drug reservoir lumen defined within thetubular intermediate portion; and a drug formulation disposed within thedrug reservoir lumen, the drug formulation comprising a drug, whereinthe elongated elastic body has a coiled retention shape in which thefirst and second ends are inwardly directed, and wherein the deviceexerts a maximum acting force less than 1 N when the device iscompressed from the coiled retention shape to a shape having a maximumdimension in any direction of 3 cm.
 22. The device of claim 21, whereinthe coiled retention shape has a maximum dimension in any direction of 6cm or less when in an uncompressed state.
 23. The device of claim 21,further comprising a nitinol wireform which imparts the coiled retentionshape to the elongated elastic body.
 24. The device of claim 21, whereinthe elongated elastic body is configured to elastically deform to aninsertion shape in which the first and second ends are directed awayfrom another for deployment of the device through a deploymentinstrument insertable through a patient's urethra.
 25. The device ofclaim 24, wherein the insertion shape in substantially linear.
 26. Thedevice of claim 21, wherein, in the coiled retention shape, the firstand second end portions of the elastic body are relatively straightcompared to the intermediate portion.
 27. The device of claim 26,further comprising a nitinol wireform which imparts the coiled retentionshape to the elongated elastic body.
 28. The device of claim 27,wherein, in the coiled retention shape, the nitinol wireform has firstand second end portions and a central portion therebetween, and thefirst and second end portions are relatively straight compared to thecentral portion.
 29. The device of claim 21, wherein the drugformulation is in the form of a plurality of mini-tablets.